Table of Contents: 13CROI

13th Conference on Retroviruses and Opportunistic Infections

Denver, Colorado - February 5-8, 2006

Cite as: Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13:abstract no. xx

Session 1—Workshop Program Committee Workshop for New Investigators and Trainees
1	HIV Molecular Virology: Mechanisms of Evasion Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 1) Ned Landau Abstract not available.
2	Principles of HIV Disease Pathogenesis Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 2) John Coffin Abstract not available.
3	Advances in Eliciting HIV-Specific Immunity Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 3) Richard Koup Abstract not available.
4	NIH Funding Opportunities for Young Investigators Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 4) Opendra Sharma Abstract not available.
5	New Developments in Antiretroviral Therapy Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 5) Scott Hammer Abstract not available.
6	Pathogenesis and Management of HIV Complications Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 6) Judith Currier Abstract not available.
Session 2—Workshop Hands-On Computer Workshop on HIV Sequence, Immunology and Vaccine Databases
7	Hands-On Computer Workshop on HIV Sequence, Immunology and Vaccine Databases Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 7) Ming Zhang, Bette Korber, Thomas Leitner, and Brian Gaschen Abstract not available.
Session 3—Symposium Dangerous Liaisons - HIV and Associated Epidemics
8	HIV AND MALARIA-WHEN ELEPHANTS COLLIDE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 8) Laurence Slutsker¹ and B Marston² Expanded resources are available for both malaria and HIV control, for example through the Global Fund for AIDS, Tuberculosis, and Malaria, and United States Government Initiatives. The public health response to the two diseases should include integration of programs where feasible. Available interventions include protection of blood supplies, provision of cotrimoxazole to people with HIV, and provision of insecticide-treated bed nets, particularly to HIV-infected pregnant women.
9	HIV AND TUBERCULOSIS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 9) Anthony Harries Strategies have been devised to decrease the joint burden of HIV and TB. First, mechanisms need to be established for collaboration between HIV/AIDS and TB programmes. Second, the burden of TB in people living with HIV/AIDS should be reduced by intensified case finding, isoniazid preventive therapy, and TB infection control in health care and congregate settings. Third, the burden of HIV in TB patients should be reduced by counselling and HIV testing, care and support of HIV-related disease, cotrimoxazole preventive therapy, and HAART. The scaling-up of HAART in sub-Saharan Africa may help to decrease case fatality and recurrence rates of TB, and may lead to a decrease in the incidence of TB, provided the difficulties of combining HAART and TB treatment can be resolved. The main difficulties include additive adverse reactions, drug interactions, and management of immune reconstitution disease. The challenge ahead lies in translating TB/HIV strategies into action.
10	PREVENTION OF PNEUMOCOCCAL DISEASE IN HIV INFECTED ADULTS AND CHILDREN Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 10) Keith Klugman While mortality and multilobar disease are related to diminishing CD4 counts, mortality comparisons with HIV-uninfected patients are confounded by severity of disease and age. Response to appropriate antimicrobial therapy is generally good if such therapy is instituted early. While trimethoprim–sulphamethoxazole prophylaxis confers significant protection from mortality, the effect of this prophylaxis on pneumococcal disease is controversial as resistance emerges rapidly. The polysaccharide pneumococcal vaccine is not protective in HIV-infected adults who are not receiving ART, but studies are underway to evaluate the protective efficacy of pneumococcal conjugates in adults. Among HIV-infected children, pneumococcal conjugate vaccine protects against invasive disease due to vaccine serotypes and has been shown to reduce the burden of lower respiratory tract infections and clinical pneumonia.
11	HIV AND CANCER Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 11) Robert Newton In resource-rich settings, the widespread use of HAART has resulted in a substantial reduction in the incidence of Kaposi’s sarcoma and non-Hodgkin lymphoma among HIV-infected people but, so far, little change in the incidence of other cancers. In resource-poor settings, where HAART is still not widely available, the incidence of HIV-associated malignancies continues to increase. For example, in Africa, where the underlying viral cause of Kaposi’s sarcoma is widespread, there has been an explosion in the incidence of the tumour with the spread of HIV. In many countries in sub-Saharan Africa, it is now the most frequently reported malignancy, more common among men in some places than all other cancers combined. In contrast, in the United States, Europe, and Australia, the incidence of Kaposi’s sarcoma among HIV-infected people has declined by at least 70% since 1997, when HAART became widely available. The risk of cancer among long-term users of HAART remains uncertain.
Session 4—Opening Plenary and Keynote Session
12	GREETINGS FROM THE PROGRAM COMMITTEE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 12) Mario Stevenson Abstract not available.
13	GLOBAL HIV-1 VARIATION AND ITS IMPLICATIONS FOR VACCINE DESIGN Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 13) Bette Korber Several promising approaches from different groups will be reviewed. Building on these concepts, a new design strategy has been developed by a team at Los Alamos that utilizes machine learning methods to create sets of artificial proteins specifically designed to maximize the number of potential T-cell epitopes in proteins incorporated in a vaccine cocktail. Theoretical results suggest a small number of proteins may have the potential to give global coverage.
14	25 YEARS OF THE HIV PANDEMIC: LESSONS LEARNED Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 14) James Curran Key biologic, behavioral, and social factors have defined the HIV/AIDS epidemic. Lessons learned from breakthroughs and barriers will be reviewed.
Session 5—Plenary
15	LESSONS LEARNED FROM IN VITRO CULTIVATION OF HEPATITIS C Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 15) Takaji Wakita This infectious HCV system provides for the first time a powerful tool with which to study the viral life cycle, to construct anti-viral strategies and to develop effective vaccines.
Session 6—Plenary
16	TEN YEARS OF HAART: PRINCIPLES FOR THE FUTURE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 16) John G Bartlett The future will bring new drugs from one of medicine's richest pipelines, simplified regimens, opt-out testing, a healthcare infrastructure in developing counties, and the potential for 30,000,000 life-years saved.
Session 7—Oral Abstracts Treatment and Clinical Complications in Pediatric and Adolescent HIV
17	PHASE I/II STUDY OF A ONCE-DAILY REGIMEN OF EMTRICITABINE, DIDANOSINE, AND EFAVIRENZ IN HIV-INFECTED, THERAPY-NAÏVE CHILDREN AND ADOLESCENTS: PACTG PROTOCOL 1021 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 17) Ross McKinney¹, M Rathore², C Hu³, P Britto³, M Smith⁴, L Serchuck⁴, J Rodman⁵, L Draper⁶, L Reynolds⁷, G Chittick⁸, and Pediatric ACTG Protocol 1021 Team A once-daily regimen of FTC, ddI, and EFV proved to be safe and effective in this 37 subject, 2-year phase I/II study. By intent-to-treat analysis, 72% of subjects demonstrated sustained HIV viral load suppression to <50 copies/mL through week 96.
18	3-NRTI HAART SIMPLIFICATION IN CHILDREN IS EFFECTIVE IN MAINTAINING VIROLOGICAL AND IMMUNOLOGICAL CONTROL AFTER 108 WEEKS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 18) Guido Castelli-Gattinara¹, M Amicosante², P Palma¹, C Cancrini², M Romiti², S Bernardi¹, A Martino¹, E Caropreso¹, and P Rossi^1,2 HAART simplification after an induction therapy allows to maintain a complete and long-term immunological and virological control with significant improvement of dyslipidemia. The progressive increase of specific cytotoxic T lymphocyte response observed in some patients can be related to an enhanced viral replication in lymph nodes or an increased frequency of blips.
19	REPEATED SUPERVISED TREATMENT INTERRUPTION WITH PROGRESSIVE INCREASES IN "OFF-TREATMENT" DURATION RESULTS IN ENHANCED VIROLOGIC CONTROL IN A SUBSET OF PEDIATRIC INDIVIDUALS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 19) William Borkowsky¹, E McFarland², R Yogev³, P Muresan⁴, L Frenkel⁵, T Fenton⁴, J Moye⁶, E Capparelli⁷, P Harding², N Ellis⁸, and the Pediatric AIDS Clinical Trials Group 1015 Team A subset of pediatric patients undergoing progressively lengthening STI demonstrated improved virologic control despite longer periods off therapy. This effect is seen in those who have had ≥13 interruptions, resulting in STI that eventually exceed 27 days in length. Enhanced HIV-specific immune responses may have played a role in this phenomenon. Selection of less replication competent virus may have played a role in one of the individuals.
20	DENDRITIC CELL FUNCTION IN SURVIVING CHILDREN AND ADOLESCENTS WITH LONG-TERM HIV INFECTION ACQUIRED PERINATALLY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 20) Seema Desai, A Chaparro, H Liu, G Scott, P Haslett, R Pahwa, and S Pahwa The most striking finding was a reduced expression of CCR7 in TLR-stimulated pDC of HIV-infected children who have poor immunologic response or ongoing, active viral replication while on ART. A defect in homing of the pDC to lymph nodes could break the link between innate and adaptive immune response to HIV.
21	PREVALENCE OF PRIMARY HIV DRUG RESISTANCE AMONG RECENTLY INFECTED ADOLESCENTS; A MULTICENTER ADOLESCENT TRIALS NETWORK STUDY: ATN029 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 21) Rolando Viani¹, L Peralta², G Aldrovandi³, B Kapogiannis⁴, R Mitchell⁵, S Spector¹, Y Lie⁶, J Weidler⁶, M Bates⁶, and C Wilson⁷ The prevalence of primary HIV resistance, particularly to NNRTI (18%), in these recently infected youth is among the highest reported in the United States. These data support the extension of current guidelines for resistance testing in HIV-infected adults, to adolescents prior to initiating HAART.
22	INCIDENCE OF TUBERCULOSIS IN HIV-INFECTED CHILDREN: THE INFLUENCE OF HAART Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 22) Neil Martinson^1,2, H Moultrieh¹, G Barry¹, A Violari¹, M Cotton³, R Van Niekerk¹, L Kalete¹, A Coovadia¹, T Meyers¹, and G Gray¹ Incidence of TB in HIV-infected children is high but few cases are confirmed. Overall, HAART protects HIV-infected children from TB but to a lesser extent than in adults. In this preliminary analysis, HAART was not protective for bacteriologically or biopsy confirmed TB. Prospective studies should confirm our findings.
23	INSULIN RESISTANCE, LIPODYSTROPHY AND ASSOCIATED METABOLIC CHANGES IN HIV-INFECTED CHILDREN Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 23) Raffaella Rosso¹, A Parodi², A Di Biagio¹, L Di Stefano¹, C Torrisi², C Dentone¹, G D'Annunzio², C Viscoli³, and M Vignolo² IR in HIV-infected children seems common and significantly different than in the control population. Fasting surrogate markers suggest increased IR as in the HIV-infected adults, which could be related to not only the cumulative ART exposure but the HIV infection itself. The association between type and duration of HAART and IR was not considered, due to the small group and the widely different type of therapy received by patients.
24	THE PRICE OF ANTIRETROVIRAL THERAPY IN CHILDREN: FOCUS ON METABOLIC MORBIDITIES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 24) Grace McComsey This overview summarizes the epidemiology, clinical presentation, and management of lipodystrophy, dyslipidemia, insulin resistance, hyperlactatemia, and decreased bone mineral density in HIV-infected children. In addition to describing the available pediatric data, this presentation will summarize and put in perspective for pediatricians the reported data on these complications from studies of HIV-infected adults.
Session 8—Oral Abstracts New Insights into Transmission and Disease Progression
25	ROUTINE HIV TESTING IN BOTSWANA: A POPULATION-BASED STUDY ON ATTITUDES, PRACTICES, AND HUMAN RIGHTS CONCERNS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 25) Sheri Weiser¹, M Heisler², K Leiter³, F Percy-De Korte³, S Tlou⁴, S Demonner², N Phaladze⁴, D Bangsberg⁵, and V Iacopino³ Routine testing is widely supported and may reduce barriers to testing in Botswana. As routine testing is adopted elsewhere, measures should be implemented to assure true informed consent, and human rights safeguards including protection from HIV-related discrimination, and protection of women against partner violence related to testing.
26	HLA-B Bw4 AND Bw6 ALLELES AND RISK FOR HIV-1 TRANSMISSION IN HIV-SERODISCORDANT HETEROSEXUAL COUPLES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 26) Tania Welzel¹, X Gao², R Pfeiffer¹, M Martin², J Goedert1, M Carrington², and T O'Brien¹ The presence of HLA-Bw4 alleles in HIV-1- infected men was associated with a decreased risk of HIV transmission from HIV-positive men to their female sex partners. It might be possible that HLA-B Bw4 allele carriers have a decreased seminal HIV RNA load which leads to a decreased HIV-1 transmission risk.
27	TRENDS IN HIV DIAGNOSIS AMONG NON-HISPANIC BLACK AMERICANS, 2001-2004 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 27) Tonji Durant, A Satcher, J Prejean, X Wei, and L Lee NHBs accounted for most HIV diagnoses from 2001 to 2004. Among NHBs, trends in transmission remained stable or declined in all categories analyzed except MSMs. However, a large disparity in HIV diagnoses remains between NHBs and other race/ethnic groups. These results underscore the impact of the HIV/AIDS epidemic on NHBs and the need to continue monitoring trends particularly among MSM, the largest transmission category. Accelerating the decline in HIV diagnoses among NHBs and narrowing the race/ethnic disparity remains a significant public health objective.
28	HIGH HIV PREVALENCE AND INCIDENCE OBSERVED AMONG AFRICAN-AMERICAN MEN WHO HAVE SEX WITH MEN (MSM) IN BALTIMORE: THE BEHAVIORAL SURVEILLANCE RESEARCH (BESURE) STUDY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 28) Frangiscos Sifakis¹, C Flynn², R Montes De Oca¹, M Hilton¹, N Tomoyasu², and D Celentano¹ HIV prevalence (32.3%) and incidence (9.2% per year) are high among MSM in Baltimore and of particular concern among African American MSM (45.6% and 15.4% per year, respectively). Unrecognized infection among African American MSM remains high (63.4%). HIV prevention and education in Baltimore must promote HIV testing and better address the needs of African American MSM.
29	NON-AIDS RELATED MORTALITY RISK EXCEEDS AIDS-RELATED MORTALITY AMONG INJECTING DRUG USERS WITH CD4+ COUNTS ABOVE 200 CELLS/MM³ Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 29) Bryan Lau^1,2, S Gange², and R Moore^1,2 Competing risk analyses indicate that non-AIDS related mortality exceeds AIDS-related mortality for those enrolling with higher CD4 counts, especially among IDU. Efforts to reduce mortality among HIV-infected populations will be hampered unless attention is also directed towards conditions that may not traditionally be considered HIV-related.
30	PRIMARY CAUSES OF MORTALITY IN HIV DISCORDANT ZAMBIAN COUPLES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 30) Philip J Peters^1,2, I Zulu^1,3, N Kancheya^1,3, S Lakhi^1,3, E Chomba^1,3, D J Kim^1,4, I Brill^1,4, J Meinzen-Derr^1,4, A Fraser-Bell^1,5, and S Allen^1,5,6 HIV positive Zambians had comparable survival times to pre-ART cohorts in high-income countries. MKC staging is a powerful, low-cost tool to identify people at high risk for death who need urgent evaluation for ART. The burden of mortality due to tuberculosis and chronic gastroenteritis highlights the need for parallel investment in tuberculosis and diarrheal disease treatment as ART scales up.
31LB	NATIONAL HIV PREVALENCE AND BED HIV INCIDENCE ESTIMATES: SOUTH AFRICA 2005 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 31LB) Thomas Rehle¹, A Puren², K Zuma¹, V Pillay¹, P Dana¹, and O Shisana¹ The addition of HIV incidence testing to the survey protocol enables a more precise and timely analysis of the current HIV-transmission dynamics and a more relevant assessment of the effect of prevention programs in South Africa.
32LB	PREVENTION OF RECTAL SHIV TRANSMISSION IN MACAQUES BY TENOFOVIR/FTC COMBINATION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 32LB) J Garcia-Lerma, R Otten, S Qari, E Jackson, W Luo, M Monsour, R Schinazi, R Janssen, T Folks, and Walid Heneine TDF/FTC combination provides a high level of protection against repeated virus challenges, demonstrating that chemoprophylaxis with potent antiretrovirals is an effective strategy for preventing sexual HIV transmission.
33LB	EFFECT OF HSV-2 SUPPRESSIVE THERAPY ON HIV-1 GENITAL SHEDDING AND PLASMA VIRAL LOAD: A PROOF OF CONCEPT RANDOMIZED DOUBLE-BLIND PLACEBO CONTROLLED TRIAL (ANRS 1285 TRIAL) Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 33LB) Nicolas Nagot^1,2, A Ouedraogo², P Mayaud¹, I Konate², L Vergne², H Weiss¹, V Foulongne³, D Djagbare², M Segongy³, P Vande Perre³, and ANRS 1285 Study Group Active HSV-2 infection is causally related to increased HIV-1 genital shedding, with implications at the systemic level. HSV-2 control interventions may contribute to reduce sexual transmissibility of HIV-1 and may delay HAART eligibility in dually infected women.
34LBa	ASSOCIATION BETWEEN GENITAL SCHISTOSOMIASIS AND HIV IN RURAL ZIMBABWEAN WOMEN Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 34LBa) Eyrun F Kjetland¹, P Ndhlovu^2,3, T Mduluza^2,3, E Gomo^2,3, N Midzi³, L Gwanzura², P Mason^2,4, L Sandvik⁵, H Friis⁶, and S Gundersen⁷ In S. haematobium-endemic areas, HIV may have spread with genital schistosomiasis, rather than STD, as an essential risk factor for heterosexual transmission. This study indicates that schistosomiasis control may perhaps be an important auxiliary in HIV prevention. The possibility of reduced HIV transmission in schistosomiasis-endemic areas adds new intervention points in the battle against HIV. Prospective studies are needed to confirm the association.
34LBb	INVESTIGATION OF REPORTS OF EXCESSIVE FALSE-POSITIVE ORAL FLUID RAPID HIV TESTS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 34LBb) Bernard Branson¹, L Wesolowski¹, K Delaney¹, M Mavinkurve², T Dowling³, and D Mackellar¹ Specificity of the OraQuick test is slightly lower with oral fluid than with whole blood, but still well above the FDA’s minimum threshold of 98% for rapid HIV tests. Investigation continues to identify site-specific factors that may lead to more FP oral fluid test results than expected.
Session 9—Oral Abstracts Studies of Pathogenic and Non-Pathogenic Infection
35	ENDEMIC INFECTION OF CENTRAL CHIMPANZEES (PAN TROGLODYTES TROGLODYTES) BY SIMIAN IMMUNODEFICIENCY VIRUS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 35) Brandon Keele¹, F Heuverswyn², Y Li¹, E Bailes³, S Loul⁴, J Brookfield³, G Shaw¹, P Sharp³, M Peeters², and B Hahn¹ SIV_cpz is widely, but unevenly distributed among wild P. t. troglodytes (but not P. t. vellerosus) apes in southern Cameroon, indicating an existing chimpanzee reservoir. Circulating SIV_cpz strains exhibit extensive genetic diversity, but form geographically defined lineages, likely reflecting P. t. troglodytes populations with non-overlapping habitats. Two of these endemically infected populations gave rise HIV-1 groups M and N, and may still serve as a source of human infection. The geographic origin of group O remains to be identified.
36	SEVERE MUCOSAL DEPLETION OF CD4+ T CELLS IN ABSENCE OF GENERALIZED IMMUNE ACTIVATION DURING NON-PATHOGENIC SIV-INFECTED SOOTY MANGABEYS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 36) Shari Gordon¹, J Engram¹, J Milush², R Dunham¹, N Klatt¹, E Strobert³, I Pandrea⁴, S Staprans¹, D Sodora², and G Silvestri¹ Natural, non-pathogenic SIV infection of sooty mangabeys is characterized by a significant depletion of CD4⁺ T cells in the MALT in the context of normal peripheral blood CD4⁺ T cell counts and the absence of generalized immune activation. These results suggest that the clinical onset of AIDS may require both the depletion of MALT-associated CD4⁺ T cells and the presence of significant mucosal or systemic immune activation.
37	DRAMATIC CD4+ T CELL DEPLETION IN THE INTESTINE IS A HALLMARK OF SIV INFECTION IN NATURAL HOSTS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 37) Ivona Pandrea¹, C Apetrei¹, J Dufour¹, N Dillon¹, J Barbercheck¹, N Katz¹, P Marx¹, V Hirsch², A Lackner¹, and R Veazey¹ Our study demonstrates that, as in rhesus macaques, in natural hosts of SIV, CD4⁺ T cell depletion occurs preferentially in the gastrointestinal tract. We therefore show for the first time that a massive CD4+ T cell depletion during primary infection at the main site of lentiviral infection does not necessarily result in progressive infection and that in natural hosts of SIV, this depletion has no significant pathogenic consequences. In hosts controlling chronic SIV infection, such as rhesus macaques infected with SIV_agm, the immune restoration in the intestine is only partial. These data call for further investigation of the mechanisms controlling the deleterious effects of SIV in both hosts.
38	HIGH FREQUENCIES OF INFECTED CD4⁺ T CELLS IN THE GASTROINTESTINAL TRACT IS ASSOCIATED WITH POOR MUCOSAL IMMUNE RECONSTITUTION AFTER HAART Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 38) Jason Brenchley¹, T Schacker², D Price¹, M Larson², A Khoruts², G Beilman², A Haase², and D Douek¹ These data strongly suggest that HAART does not adequately suppress viral replication at mucosal surfaces and this residual viral replication maintains the depletion of mucosal CD4⁺ T cells. Moreover, this continued depletion may be related to high levels of infection within blood CD4⁺ T cells with a mucosal homing phenotype. Taken together, these data explore the dynamics of reconstitution between different anatomical sites and suggest that ongoing viral replication at particular sites may impair immune reconstitution.
39	INITIATION OF HAART DURING PRIMARY HIV-1 INFECTION RESULTS IN BETTER RESTORATION AND MAINTENANCE OF MUCOSAL CD4⁺ T CELLS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 39) M Guadalupe¹, E Reay¹, S Sankaran¹, M George¹, B Shacklett¹, J Flamm², J Wegelin¹, T Prindiville¹, Satya Dandekar¹, and S Dandekar¹ Our findings indicate that initiation of HAART during primary HIV-1 infection was more effective in restoring or maintaining mucosal CD4+ T cells and suppressing viral loads than initiation during chronic HIV-1 infection. Furthermore, these data emphasize the importance of monitoring clinical disease progression in lymphoid tissues as well as peripheral blood for a more accurate assessment of the efficacy of HAART.
40	RESTORATION OF MEMORY CD4⁺ CCR5⁺ T CELLS IN THE GASTROINTESTINAL TRACT DURING THE CHRONIC STAGE OF SIV INFECTION PREDICTS LONG-TERM NON-PROGRESSION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 40) Binhua Ling, R Veazey, M Hart, M Kuroda, B Pahar, and P Marx Profound depletion of memory CD4⁺CCR5⁺ cells in GALT was indistinguishable between disease progressors and LTNP at the acute stage of infection. Restoration of mucosal memory CD4⁺CCR5⁺ cells during the chronic phase predicted LTNP. Sufficient CD8⁺ T cells may be essential for controlling SIV infection in GALT and required for restoration of memory CD4⁺CCR5⁺ T cells.
41	CD4⁺ T-CELL QUANTIFICATION WITHIN GUT LAMINA PROPRIA OF HIV PATIENTS AFTER HAART Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 41) Jason Baker, M Larson, A Khoruts, A Haase, and T Schacker The effector memory CD4⁺ T cells in GALT are rapidly depleted, and our data suggest a limited capacity for repletion with HAART. Further work is required to understand the reasons why repletion of the gut is limited compared to the peripheral expansion of the total CD4⁺ T-cell population, and if a longer duration of HAART would result in better recovery of CD4⁺ T cells in secondary lymphatic tissues.
42	AIDS-DEFINING CD4 T-CELL LEVELS CORRELATE WITH EXPANDED CO-RECEPTOR USAGE DURING NONPATHOGENIC SIV_sm INFECTION OF SOOTY MANGABEYS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 42) Jeffrey Milush¹, J Reeves², D Zhou¹, A Muthukumar¹, E Chacko¹, S Gordon³, K Stefano-Cole⁴, S Staprans³, G Silvestri³, and D Sodora¹ These data indicate that expanded co-receptor usage can occur in SIV-infected sooty mangabeys. Moreover, CD4 levels <100/mL blood are likely sustained by direct viral killing of T-cell targets; bystander-associated cell death does not appear to play a major role. The CD4^low sooty mangabeys provide evidence that AIDS-defining CD4 levels and progression to clinical AIDS can be separated; increased immune activation that occurs in HIV⁺ humans, but not in sooty mangabeys, appears to be crucial for progression to AIDS.
43	CXCR4-TROPIC VIRUSES ARE COMMON AMONG ANTIRETROVIRAL TREATED PATIENTS WITH DETECTABLE VIREMIA AND ASSOCIATED WITH LOWER TREATMENT-MEDIATED CD4 GAINS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 43) Peter Hunt¹, J Martin¹, M Bates², W Huang², S Spudich¹, R Price¹, D Williamson³, E Sinclair³, R Hoh¹, and S Deeks¹ Treated patients with partial viral suppression are more likely than untreated patients to harbor dual/mixed or X4-tropic viruses, independent of the extent of current or prior immunodeficiency. Dual/mixed or X4 tropism is also associated with fewer treatment-mediated CD4+ T cell gains, perhaps due to a greater ability to deplete resting memory and naïve CD4 cells.
44LB	THE EFFECT OF HIV SUBTYPE ON RAPID DISEASE PROGRESSION IN RAKAI, UGANDA Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 44) Oliver Laeyendecker¹, X Li², M Arroyo³, F McCutchan³, R Gray², M Wawer⁴, D Serwadda⁵, F Nalugoda⁶, G Kigozi⁶, T Quinn¹, and Rakai Health Science Program Viral load had a significant effect on disease progression over longer follow-up time, but did not predict death within 24 months of infection. Subtype D and recombinant strains incorporating subtype D are pathogenic than subtype A, probably due to the increased frequency X4 co-receptor tropism in subtype D. These findings suggest that knowledge of HIV subtype might be useful in clinical management of HIV infection in Uganda.
Session 10—Oral Abstracts and Research Overview Antiretroviral Therapy I: New Agents and New Insights
45	GS9148: A NOVEL NUCLEOTIDE ACTIVE AGAINST HIV-1 VARIANTS WITH DRUG-RESISTANCE MUTATIONS IN REVERSE TRANSCRIPTASE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 45) Tomas Cihlar¹, A Ray¹, D Boojamra¹, L Zhang¹, H Hui¹, D Grant¹, K White¹, M Desai¹, N Parkin², and R Mackman¹ GS9148 exhibits a favorable in vitro pharmacological profile including lower levels of resistance than approved NRTIs, an indication of potential efficacy against existing NRTI-resistant viruses. The amidate prodrug of GS9148 is an attractive candidate for further development with potential for once daily dosing and activity in both treatment-naïve and NRTI-experienced patients.
46	1-(β-D-DIOXOLANE) THYMINE IS EFFECTIVE AGAINST HIV-1-CONTAINING TAM AND M184V Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 46) Johan Lennerstrand¹, G Bluemling¹, M Ruckstuhl¹, M Bennett¹, C Chu², and R Schinazi¹ Compared with other RT inhibitors, DOT-TP was overall more effective against RT-containing TAM, M184V, and K65R. The 69-mutant demonstrated a lower level of resistance to DOT-TP than AZT-TP and TFV-DP. However, as expected for dioxolane nucleosides, an increased non-ATP-dependent resistance was found with the 151-mutant. These enzymatic studies indicate that DOT resistance mainly involves binding discrimination and only modest ATP-dependent excision.
47	NUCLEOTIDE-COMPETING REVERSE TRANSCRIPTASE INHIBITORS FORM A STABLE DEAD-END COMPLEX WITH THE HIV-1 ENZYME Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 47) M Ehteshami¹, J Deval¹, S Barry¹, D Jochmans², K Hertogs², and Matthias Götte¹ The results provide strong evidence to suggest that NcRTI-1 can partially occupy the nucleotide binding site of HIV-1 RT. The compound forms a dead-end complex that prevents the incorporation of dNTP substrates. Our biochemical data are consistent with cell-based inhibition measurements showing that the M184V change is associated with decreased susceptibility to NcRTI-1, while K65R confers hypersusceptibility.
48	NEXT GENERATION HIV PEPTIDE FUSION INHIBITOR CANDIDATES ACHIEVE POTENT, DURABLE SUPPRESSION OF VIRUS REPLICATION IN VITRO AND IMPROVED PHARMACOKINETIC PROPERTIES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 48) Mary Delmedico¹, B Bray¹, N Cammack², D Davison¹, J Dwyer¹, L Frick¹, N Tvermoes¹, S Wring¹, H Zhang¹, and M Greenberg¹ TR-290999 and TR-291144 demonstrate: potent in vitro antiviral activity; durable in vitro control of virus replication; and slow, extended clearance properties in monkeys. The combination of potency, durability, and pharmacokinetic and appropriate physical properties enables the evaluation of sustained-release formulations to provide once/week dosing. Further study of these novel, next-generation fusion inhibitors is in progress.
49LB	DEVELOPMENT OF NOVEL ORALLY BIOAVAILABLE CXCR4 ANTAGONISTS, KRH-3955 AND KRH-3140: BINDING SPECIFICITY, PHARMACOKINETICS AND ANTI-HIV-1 ACTIVITY IN VIVO AND IN VITRO Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 49LB) Yuetsu Tanaka¹, K Okuma¹, R Tanaka¹, S Kumakura², A Shimoyamada², K Hirose², M Yanaka², T Murakami³, and N Yamamoto³ KRH3955 and KRH-3140 are orally bioavailable CXCR4 antagonists with potent anti-X4 HIV-1 activities in vivo, indicating that these drugs may be desirable additives to an anti-HIV-1 therapy.
50LB	EXECUTION OF A HIGH THROUGHPUT HIV-1 REPLICATION SCREEN AND THE IDENTIFICATION OF A NOVEL SMALL MOLECULE INHIBITOR THAT TARGETS HIV-1 ENVELOPE MATURATION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 50LB) Wade Blair, J Cao, L Jackson, Q Peng, J Isaacson, S Butler, H Wu, A Chu, and A Patick UK-201844 represents the prototype for a unique HIV-1 inhibitor class that directly or indirectly inhibits HIV-1 gp160 processing, resulting in the production of virions with non-functional Env proteins.
51	TOWARD GENE KNOCK-OUT THERAPY FOR AIDS/HIV: TARGETED DISRUPTION OF CCR5 USING ENGINEERED ZINC FINGER PROTEIN NUCLEASES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 51) Yann Jouvenot¹, E Perez², F Urnov¹, J Miller¹, E Rebar¹, M Holmes¹, D Ando¹, J Riley², P Gregory¹, and C June² The frequency of gene disruption observed supports its examination as a possible method for the therapeutic modification of isolated patient cells to generate HIV-resistant T cells or hematopoietic precursors.
52	PHARMACOKINETICS/PHARMACODYNAMICS OF PA-457 IN A 10-DAY MULTIPLE DOSE MONOTHERAPY TRIAL IN HIV-INFECTED PATIENTS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 52) Patrick Smith¹, A Forrest¹, G Beatty², J Jacobson³, J Lalezari⁴, J Eron⁵, R Pollard⁶, M Saag⁷, J Doto⁸, and D Martin⁸ PA-457 demonstrated significant antiviral activity at the higher dose levels, with greater activity observed with increasing drug exposure. Additional antiviral activity is likely with doses higher than those used in this trial, as E_max was not reached at 200 mg. Similar to other available ART, pharmacokinetics/pharmacodynamics appears to be an important determinant of PA-457 activity. Additional studies to evaluate the potential role of PA-457 in the treatment of HIV-infection are warranted.
53	THE ROLE OF DRUG INTERACTION STUDIES IN EARLY ANTIRETROVIRAL DRUG DEVELOPMENT Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 53) Kimberly Struble Drug interaction information is important for the safe use of combination ART. Early identification of potential interactions and appropriate clinical management of these interactions can lead to more effective long-term therapy by reducing drug toxicity or by delaying the development of resistance in antiretroviral naïve and experienced patients.
Session 14—Symposium HIV Prevention Research: New Advances, Continued Challenges
54	ANTIRETROVIRAL THERAPY TO PREVENT SEXUAL TRANSMISSION OF HIV Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 54) Myron Cohen These concerns notwithstanding, the public health opportunities for ART as prevention are substantial, and ongoing research is likely to improve this important application.
55	BEYOND CONDOMS: CHEMICAL AND PHYSICAL BARRIERS TO PROTECT WOMEN FROM HIV Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 55) Sharon Hillier There is a growing consensus that a highly effective female-controlled method will require a combination of products or methods, and combining cervical barriers and microbicides offers a compelling approach to HIV/ sexually transmitted infections prevention. Additional work is focused on development of microbicides, which are not coitally dependent.
56	VACCINES TO INDUCE CTL RESPONSES TO HIV IN IMMUNOCOMPETENT INDIVIDUALS: STATE OF THE FIELD Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 56) Lawrence Corey The 2 leading candidates are a recombinant Ad5 vector containing gag-pol-nef made by Merck Corporation, and a multivalent DNA followed by Ad5 vaccine made by the NIH Vaccine Research Center. These vaccines are entering advanced clinical trials and a review of their immunogenicity and approaches to evaluate their potential efficacy in humans will be discussed.
57	HIV VOLUNTARY TESTING AND COUNSELING (VCT) DIVIDES, BUT IT SHOULD UNITE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 57) Thomas Coates The presentation will conclude with ongoing and needed research in HIV VCT, with an emphasis on the tension between the preventive and diagnostic aims of HIV VCT, and the kinds of research needed to resolve and eliminate such tension.
Session 15—Symposium Cellular Co-Factors and Innate Resistance
58	HIV INFECTION OF NON-DIVIDING CELLS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 58) Michael Emerman, and M Yamashita Thus, we showed that Gag is the major determinant for the ability of retroviruses to infect non-dividing cells, and suggest that uncoating, rather than nuclear import is the rate-limiting step.
59	RESTRICTION OF RETROVIRUS REPLICATION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 59) Jonathan Stoye, M Yap, M Dodding, and S Okhura The critical interaction between CA and Trim-CypA appears to take place soon after viral entry. Quantitative PCR analysis on viral reverse transcriptase products revealed that the different fusion proteins block HIV-1 at two distinct stages of its lifecycle. Both blocks are distinguishable from that associated with Fv1. With Trim1 and Trim18, timing of replication arrest is dependent on the length of the Trim component of the fusion protein. These observations suggest that restriction factor binding can have different mechanistic consequences.
60	EVOLUTION OF INTRINSIC IMMUNITY AGAINST RETROVIRUSES IN PRIMATE GENOMES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 60) Harmit Malik, S Sawyer, M OhAinle, J Kerns, L Wu, and M Emerman We have been able to use the signature of rapid evolution to identify a small “patch” in the TRIM5α protein that is responsible for antiviral specificity, highlighting the power of such evolutionary analyses. Screening human populations for genetic variation in TRIM5α, we uncovered an impaired allele at an unexpectedly high frequency (~50%) in certain ethnic groups. We can use the evolutionary insights gained from APOBEC3G and TRIM5α, as well as human population genetics, to identify other, novel restriction factors employed for retroviral defense by primate genomes.
61	NEW INSIGHTS INTO THE ANTIVIRAL ACTION OF APOBEC3G Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 61) Warner Greene, Y L Chiu, J Kreisberg, V Soros, M Santiago, K Stopak, and W Yonemoto These results indicate that the post-entry restricting activity afforded by LMM A3G is temporarily inactivated resting CD4 T cells present in lymphatic tissues. Our studies indicate that the local production of select cytokines including interleukin (IL)-2 and IL-15 in these lymphatic tissues plays a key role in the induced assembly of HMM A3G complexes. Addition of higher concentrations of IL-2, IL-15, or IL-7 as single stimuli also activates A3G gene expression leading to the induction of A3G mRNA and protein expression.
Session 16—Oral Abstracts Implementing Antiretroviral Therapy in Developing Countries
62	ADHERENCE TO NNRTI-BASED REGIMENS AND VIROLOGIC OUTCOMES IN HIV-INFECTED SOUTH AFRICAN ADULTS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 62) Jean Nachega¹, M Hislop², L Rengensberg², R Chaisson³, and G Maartens⁴ High levels of adherence, as assessed by pharmacy claim data in a private-sector management program, strongly predict viral suppression in HIV-positive South African adults on NNRTI-based ART. Pharmacy records are a simple and a valid program-level adherence monitoring tool.
63	MORTALITY AND CAUSES OF DEATH IN ADULTS RECEIVING HAART IN SENEGAL: A 7-YEAR COHORT STUDY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 63) J F Etard^1,2, A Dieng², A Diouf², M Thierry-Mieg², V Cilote^2,3, B Taverne^1,2, S Mboup⁴, I Ndoye⁵, Eric Delaporte¹, P Sow⁴, and ANRS 1290 This study underlines the early mortality pattern after HAART initiation, reports long-term trend in mortality and its predictors among patients under HARRT in an African setting, and highlights the leading role of mycobacterial infections in the causes of death.
64	RAPID SCALE-UP OF ANTIRETROVIRAL SERVICES IN ZAMBIA: 1-YEAR CLINICAL AND IMMUNOLOGIC OUTCOMES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 64) Moses Sinkala¹, J Levy², I Zulu³, A Mwango¹, E Stringer², B Chi², S Reid², T Ellerbrock⁴, M Bulterys⁵, and J Stringer² Rapid initiation of ART in a programmatic setting led to favorable clinical outcomes at 6 and 12 months in Zambia. Advanced HIV disease was a very strong predictor of mortality in this population, suggesting that every effort should be made to identify and treat infected patients earlier in their disease course.
65	PERFORMANCE CHARACTERISTICS OF NON-CD4-BASED CRITERIA FOR INITIATION OF ART IN AN AMBULATORY CLINIC POPULATION IN PHNOM PENH, CAMBODIA Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 65) Chel Sarim¹, J Elliott¹, S Huffam¹, H Chenda¹, P Sophea¹, S Vonthanak¹, J Kaldor², D Cooper², and M Vun¹ Basing initiation of ART on clinical criteria alone would have resulted in poor treatment decision-making in this population. Addition of lymphocyte count improved performance, but treatment misallocation remained substantial. These data strongly support the role of CD4 testing in criteria for initiation of ART in an ambulatory setting.
66	REGIMEN DURABILITY AND TOLERABILITY TO 36-MONTH DURATION ON ART IN KHAYELITSHA, SOUTH AFRICA Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 66) Andrew Boulle¹, G Van Cutsem², D Coetzee¹, K Hilderbrand^1,2, E Goemaere², and G Maartens³ The substitution of AZT with d4T in the first-line regimen has resulted in fewer regimen changes due to anemia or neutropenia, and correspondingly a higher proportion of changes due to peripheral neuropathy and lactic acidosis. The incidence of symptomatic hyperlactatemia or lactic acidosis is higher in this cohort than that anticipated from the literature. There is generally a clinical delay in switching to second-line compared with the point that virological failure is confirmed on laboratory criteria. The Khayelitsha cohort provides an opportunity to reliably explore regimen durability and tolerability to 36 months in the context of treatment in a developing country.
67	WHEN ARE ADULTS IN RESOURCE-CONSTRAINED SETTINGS MOST LIKELY TO EXPERIENCE AN HIV-ASSOCIATED ILLNESS FOLLOWING HAART INITIATION AND WHAT IS IT RELATED TO? Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 67) Paula Braitstein¹, M Brinkhof¹, M Schechter^2,3, N Kumarasamy⁴, D Nash⁵, A Boulle⁶, E Ekong⁷, F Dabis⁸, E Balestre⁸, M Egger¹, and the Antiretroviral Treatment in Lower Income Countries (ART-LINC) Collaboration Although the completeness of ascertainment of HIV-associated illness events in ART-LINC is unclear at the moment, and diagnostic criteria differ across centers, these results indicate a considerably higher risk of new HIV-associated illness and TB events during months 1 to 2 than later months post-HAART. The increased risk early on may be associated with the immune reconstitution syndrome. Age, sex, baseline CD4 count, initial treatment regimen, and having a history of HIV-associated illness or TB at baseline were important predictive factors.
68	TUBERCULOSIS AMONG HIV-INFECTED PATIENTS RECEIVING HAART: LONG-TERM INCIDENCE AND RISK FACTORS IN A SOUTH AFRICAN COHORT Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no.68) Stephen Lawn^1,2, M Badri¹, and R Wood¹ TB incidence continued to decrease during the first 5 years of HAART, with a 3.5-fold reduction occurring beyond the first year of treatment. HAART may therefore contribute more to TB control in low-income countries than has previously been estimated. Patients with advanced pre-treatment immunodeficiency had persistently increased risk of TB during HAART and TB occurred among those with poor immunological recovery during HAART. Advanced immunodeficiency among patients accessing HAART in low-income countries may limit immune recovery and lead to chronically heightened risk of TB.
69	PREVALENCE OF HIV AND UNDIAGNOSED TUBERCULOSIS IN A PERI-URBAN COMMUNITY IN SOUTH AFRICA Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 69) Linda-Gail Bekker¹, K Middelkoop¹, L Myer², A Whitelaw², A Grant³, G Kaplan⁴, S Lawn^1,3, and R Wood¹ This community has a very high prevalence of both TB and HIV and there are more individuals in the community with undiagnosed TB than individuals already on treatment. The majority of individuals with previously undiagnosed TB are HIV-uninfected, while the known cases are predominantly HIV-infected.
Session 18—Plenary
70	WHERE AIDS CAME FROM Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 70) Paul Sharp The closest SIV_cpz relatives of HIV-1 infect one particular subspecies of chimpanzees, Pan troglodytes troglodytes, in West Central Africa. We have now found widespread endemic infection in these apes, with SIV_cpz prevalence rates over 20% in some communities. SIV_cpz strains exhibit a local phylogeographic clustering, allowing us to trace the origins of pandemic (group M) and nonpandemic (group N) HIV-1 to distinct, geographically isolated chimpanzee communities in southern Cameroon. Thus, 25 years into the AIDS epidemic, the origins of this newly emerged disease have been elucidated.
Session 19—Plenary
71	AIDS RESTRICTION GENES: DISCOVERY, ASSESSMENT AND IMPLICATIONS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no.71) Stephen O'Brian This presentation will describe the validity, attributes, and applications of these genes for the AIDS epidemic. In addition, further applications of ARGs based on selection signatures, mitochondrial DNA, and Y-chromosome influences will be described. Finally, a preview of a whole genome scan for undiscovered ARGs in the context of the recently annotated human Hap Map will be discussed.
Session 20—Oral Abstracts and Research Overview Neuropathogenesis: Viral Dynamics and Host Responses
72	HIGH CEREBROSPINAL FLUID NEUROFILAMENT PROTEIN LEVELS IN AIDS DEMENTIA COMPLEX Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 72) Magnus Gisslén¹, P Cinque², L Hagberg¹, R Price³, L Rosengren¹, and B Brew⁴ The findings of this study support the value of CSF NFL as a useful marker of CNS damage in HIV infection. In patients without central nervous system opportunistic infections or tumors, elevated CSF NFL concentrations are associated with ADC, follow the grade of severity, and decrease after initiation of effective ART. Virtually all previously suggested CSF markers of ADC relate to immune activation or HIV viral load. NFL is the first marker that directly reflects brain injury; as such, CSF NFL levels should prove to be useful in clinical practice as an objective marker of ADC.
73	LEPTIN AND NEUROPSYCHOLOGICAL PERFORMANCE: A NEW BIOMARKER FOR COGNITIVE FUNCTION? Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 73) Jeannie Huang, S Letendre, J Beck, M Cherner, S Kolakowski, R Ellis, and HIV Neurobehavioral Res Group Decreased CSFL and CSLR are associated with neurocognitive deficits, specifically in memory and learning. Leptin may be important for memory and learning in humans, and may be useful as a clinical biomarker for neurocognitive function.
74	BETTER ANTIRETROVIRAL PENETRATION INTO THE CENTRAL NERVOUS SYSTEM IS ASSOCIATED WITH LOWER CSF VIRAL LOAD Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 74) Scott Letendre¹, E Capparelli¹, B Best¹, D Clifford², A Collier³, B Gelman⁴, J McArthur⁵, J McCutchan¹, D Simpson⁶, R Ellis¹, and the CHARTER Group These findings support that better penetration of ART across the blood-CSF barrier leads to better control of HIV replication in CSF. Since inhibition of HIV replication in the CNS is important in treating patients who have HIV-associated neurocognitive disorders, they may benefit from CNS-targeted ART therapy.
75	DISCORDANCE OF GENOTYPIC RESISTANCE BETWEEN CSF AND PLASMA VIRUS IN A MULTICENTER OBSERVATIONAL COHORT Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 75) Joseph Wong^1,2, S Pillai^1,2, R Ellis³, D Clifford⁴, A Collier⁵, B Gelman⁶, J McArthur⁷, J McCutchan³, S Morgello⁸, I Grant³, and the CHARTER Group Discordant resistance between CSF and plasma virus were frequently observed in this North American cohort in the absence of active CNS co-morbidities. These findings indicate that compartmentalization of HIV replication is not wholly dependent on variable ART penetration because classes of poorly penetrating ART (i.e., PI) did not differ from others, and because genetic distances between CSF and plasma virus sequences were at times large even in the absence of drug resistance mutations. The clinical implications of these findings remain to be determined.
76	THE HIV ENV N283 GENETIC VARIANT IS ASSOCIATED WITH BRAIN INFECTION AND DEMENTIA Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 76) Rebecca Dunfee^1,2, E Thomas^1,2, P Gorry^1,2, J Taylor³, K Kunstman³, J Bell⁴, S Wolinsky³, and D Gabuzda^1,2 The HIV env N283 genetic variant is associated with brain infection and HAD. N283 enhances macrophage and microglia tropism by increasing gp120-CD4 affinity through contact with Q40 of CD4. These results lead to a better understanding of mechanisms that underlie HIV neurotropism.
77	LONGITUDINAL ANALYSIS OF ENV POPULATION DYNAMICS IN BLOOD AND CEREBROSPINAL FLUID OF SIV_sm-INFECTED MACAQUES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 77) Patrick Harrington¹, M Connell², P Johnson², R Meeker¹, and R Swanstrom¹ SIV_sm populations are present in CSF early in infection, with no evidence of a genetic bottleneck for CSF invasion from the periphery. Furthermore, SIV_sm populations in CSF can emerge and turn over rapidly. Even so few animals, we observed different relationships between the blood plasma and CSF viral populations over the course of infection: close concordance over a prolonged period of time versus rapid discordance.
78	HEMOCHROMATOSIS GENE POLYMORPHISMS AND PERIPHERAL NEUROPATHY DURING ART: ANALYSIS NWCS 238 OF ACTG STUDY 384 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 78) Asha R. Kallianpur¹, T Hulgan¹, J Canter², M Ritchie², J Haines², G Robbins³, R Shafer⁴, D Clifford⁵, D Haas¹, and the AIDS Clin Trials Group Iron-loading HFE polymorphisms may be associated with a decreased risk of NRTI-associated peripheral neuropathy. This finding has potential implications for the prevention and management of NRTI-associated peripheral neuropathy, particularly among populations at risk for iron deficiency. Further study of functional mechanisms and confirmation of this association in other cohorts are warranted.
79	CONTROLLED STUDY OF HIGH-CONCENTRATION CAPSAICIN PATCH FOR PAINFUL HIV-ASSOCIATED DISTAL SENSORY POLYNEUROPATHY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 79) David Simpson¹, S Brown², S Chang³, J Jermano³, and C107 Study Group This controlled trial in painful HIV DSP shows that CDP produces significant and durable pain reduction with good tolerability. CDP may provide a new mode of effective treatment for this disabling disease.
80	UPDATE ON SENSORY NEUROPATHIES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 80) Justin McArthur Currently, there are no effective therapies for HIV-SN except for symptomatic control with anticonvulsants, selective antidepressants, or topical capsaicin (in high concentration). The hormone erythropoietin (EPO) prevents sensory axonal degeneration and in vitro neuronal death by both gp120 and ddC. EPO may be useful in the treatment of HIV-SN, and a controlled trial is underway.
Session 21—Oral Abstracts Hepatitis Viruses Complicating HIV Infection
81	UTILITY OF THE EARLY VIRAL RESPONSE TO INDIVIDUALLY ADJUST THE DURATION OF TREATMENT FOR CHRONIC HEPATITIS C, GENOTYPE 2 OR 3, IN HIV-CO-INFECTED PATIENTS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 81) Manel Crespo, J Esteban, E Ribera, V Falcó, A González, S Villar Del Saz, I Ocaña, and A Pahissa Early viral response appears as a useful tool to individually adjust the duration of treatment for chronic hepatitis C, genotype 2 or 3, in HIV-co-infected patients. In our study, high SVR and low viral relapse rates were observed after 24 weeks of therapy among those patients with undetectable viral load at week 4.
82	SERUM IP-10 LEVEL IS ASSOCIATED WITH DISTINCT EARLY VIRAL DYNAMICS IN HCV AND HCV/HIV-INFECTED SUBJECTS TREATED WITH IFN-α Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 82) Benigno Rodriguez¹, H Valdez², K Milkovich¹, N Yonkers¹, A Post³, R Bonomo^3,4, D Bobak³, L Jones⁴, S Giulianetti⁴, and D Anthony^1,4 HIV co-infection is associated with reduced 2-day HCV decline in pegIFN-treated subjects despite high initial IFN-α doses and serum IP-10 level increases consistent with a preserved downstream IFN-α effect. This suggests greater resistance to the effect of IFN-α2b in co-infected patients. IFN-γ HCV-specific responses are also diminished in co-infected patients, perhaps reflecting synergistic immune impairments due to both infections. Because relationships exist both between baseline serum IP-10 level and HCV level and between serum IP-10 increase and early HCV RNA decline, host IFN-α responsiveness at baseline may be predictive of IFN-α therapy virologic outcome.
83	EFFECTS OF CYTOKINE GENE POLYMORPHISMS ON TREATMENT OF ACUTE HEPATITIS C INFECTION IN HIV-INFECTED PATIENTS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 83) Jacob Nattermann¹, M Vogel¹, G Ahlenstiel², M Schulz¹, T Sauerbruch¹, U Spengler¹, J Rockstroh¹, and Kompetenznetz HIV/AIDS Response rates to interferon-alpha therapy are enhanced in acute HCV-infected HIV+ patients carrying the IL6 high producer genotype. This might be explained by the IL-6 mediated activation of signal transducers and activators of transcription (STAT), which have been shown to be essential for the antiviral effect of interferons and induction of anti-HCV activity in liver cells.
84	VIRUS-SPECIFIC T-CELL RESPONSES AND LOSS OF SPONTANEOUS CONTROL OF HCV IN HIV+ INDIVIDUALS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 84) Arthur Kim, J Schulze Zur Wiesch, T Allen, R Gandhi, B Davis, A Jones, G Robbins, R Chung, G Lauer, and B Walker HIV-1-infected individuals with spontaneous control of HCV are at risk for recurrence of HCV viremia. This finding highlights the need for repeat viral load testing for controllers of HCV, particularly if coinfected, and provides a possible explanation for the higher rate of HCV persistence observed in this population. Our results also suggest that avoidance of low nadir CD4 counts may preserve memory lymphocytes against HCV that contribute to HCV control in coinfected persons.
85	ENHANCED REPLICATION OF GB VIRUS C IN HIV-INFECTED PATIENTS RECEIVING HAART Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 85) Per Björkman¹, V Letelier Molnegren¹, A Marshall¹, L Flamholc¹, N Güner², and A Widell¹ GBV-C viral load increases during HAART-induced suppression of HIV replication and decreases during treatment interruptions. This suggests that replication of GBV-C could be suppressed during progressive HIV infection, and supports the hypothesis that GBV-C RNA status may be secondary to HIV disease progression.
86	EVIDENCE FOR SEXUAL TRANSMISSION OF HCV IN RECENT EPIDEMIC IN HIV-INFECTED MEN IN THE UK Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 86) Mark Danta¹, D Brown¹, G Dusheiko¹, O Pybus², M Nelson³, M Fisher⁴, A Johnson¹, C Sabin¹, and S Bhagani⁵ High-risk and mucosally traumatic sexual factors are significantly associated with the recent transmission of HCV. The co-circulating HCV lineages identified by phylogenetic analysis belong to different subtypes and genotypes, indicating that the epidemic is not caused by viral genetic change, but rather patient factors such as sexual or drug behavior. These patient factors should be the focus of education-based public health interventions.
87	RISE IN HCV INCIDENCE IN HIV-INFECTED MEN WHO HAVE SEX WITH MEN IN AMSTERDAM: SEXUAL TRANSMISSION OF DIFFICULT TO TREAT HCV GENOTYPES 1 AND 4 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 87) R Coutinho¹ and Thijs van de Laar² The incidence of HCV has significantly increased in HIV+ but not in HIV MSM in Amsterdam. The high degree of clustering observed in phylogenetic analysis provides strong evidence for the introduction and sexual transmission of different co-circulating HCV lineages. HIV infection and/or mucosal trauma caused by extreme sexual techniques and concurrent STD might facilitate sexual transmission of HCV. Increased incidence of mainly difficult to treat HCV genotypes 1 or 4 in HIV+ MSM might have serious implications for both individual and public health.
88	SYSTEMIC OVERVIEW OF HAART-ASSOCIATED LIVER ENZYME ELEVATIONS IN PATIENTS INFECTED WITH HIV AND CO-INFECTED WITH HCV Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 88) Yves Benhamou¹, V Mats², and D Walczak³ HIV co-infection but not baseline ALT is a strong predictor of HAART-related LEE. Among HIV-infected patients, the percentage of LEE increased as follows: NRTI<BPI<PI<NNRTI. The same order exists in HCV co-infected patients, but differences were not significant.
Session 22—Oral Abstracts and Research Overview Immunological Correlates of Protection: What Works and What Doesn't
91	LACK OF NEUTRALIZING ANTIBODY RESPONSE TO HIV-1 PREDISPOSES TO SUPERINFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 91) Davey Smith¹, M Strain², S Frost¹, S Pillai³, J Wong³, T Wrin⁴, C Petropoulos⁴, E Daar^5,6, S Little¹, and D Richman^1,7 All 3 individuals identified with HIV superinfection had less cross-protective and autologous neutralizing antibody response than their non-superinfected case-controls. These data identify cross-protective neutralizing antibody in the prevention of superinfection and elucidate important goals for protective vaccine design.
92	BROAD NEUTRALIZATION OF HIV-1 VARIANTS IN COUPLES WITHOUT EVIDENCE OF SYSTEMIC SUPERINFECTION DESPITE EXPOSURE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 92) J McConnell¹, Y Liu², C Kreis¹, J Marcus¹, L Bragg¹, C Chappey², E Stawiski², T Wrin², F Hecht³, and Robert Grant¹ We observed development of broad neutralization activity during the first 2 years of infection, including activity against viruses in sexual partners. Broad serum neutralizing responses may be a mechanism that blocks superinfection in chronically infected couples and other highly exposed individuals.
93	NON-NEUTRALIZING ANTIBODY THAT PREVENTS SIV INFECTION IN NEONATAL RHESUS MACAQUES POTENTLY INHIBITS SIV IN THE PRESENCE OF RHESUS MACAQUE EFFECTOR CELLS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 93) Donald Forthal¹, G Landucci¹, K Stefano Cole², J Becerra¹, M Marthas³, and K Van Rompay³ These results demonstrate, for the first time, that antibodies that do not neutralize pathogenic strains of SIV may nonetheless have potent anti-viral activity mediated by interactions between antibody Fc and Fc receptors on rhesus macaque cells, such as monocytes and natural killer cells. Since infusion of SIV-HIS prevents SIV_mac251 infection in the absence of neutralizing activity, these results suggest that antibody-dependent, cell-mediated virus inhibition is a protective immune function against primate lentivirus infection.
94	SIMIAN IMMUNODEFICIENCY VIRUS ENGRAFTED WITH HIV-1-SPECIFIC EPITOPES: REPLICATION, NEUTRALIZATION, AND SURVEY OF HIV-1+ PLASMA Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 94) E Yuste¹, H Sanford¹, J Bixby¹, S Little², M Zwick³, T Greenough⁴, D Burton³, D Richman^2,5, R Desrosiers¹, and Welkin Johnson¹ We have confirmed by direct analysis that neutralizing activities of the 2F5 and 4E10 specificities are either rare among HIV-1+ individuals or, if present, represent a small fraction of the total neutralizing activity in a given plasma sample. The parental SIV₂₃₉ and neutralization-sensitive SIV₃₁₆ control viruses were also not neutralized, indicating that significant cross-reactive neutralizing activity is not present in HIV+ patient plasma. Our results also suggest that the Env spikes of SIV₂₃₉ and HIV-1 are structurally similar, and that resistance of SIV₂₃₉ and HIV-1 primary isolates to antibody-mediated neutralization arises from similar mechanisms.
95	DEFINING AND MEASURING HIV-1 ESCAPE FROM CTL: EPITOPE-DEPENDENT AVIDITY THRESHOLDS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 95) M Bennet, H Ng, A Ali, and Otto O. Yang These data indicate that the functional avidity required for the antiviral activity of HIV-1-specific CTL varies depending on the epitope. When assessing for viral escape due to epitope mutation the absolute change in avidity is not sufficient; the relationship of avidity to the KE₅₀ better reflects whether CTL recognize the variant. Furthermore, greater avidity above the avidity threshold does not yield greater antiviral activity, consistent with the function of T-cell receptor binding as a simple trigger for CTL activity.
96	LOCALIZED POPULATIONS OF CD8- SIV-SPECIFIC T CELLS IN LYMPHOID FOLLICLES AND VAGINAL EPITHELIUM Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 96) Pamela Skinner¹, T Mattila¹, C White¹, A Hage¹, R Sunderman¹, D Watkins², C Miller³, E Connick⁴, and A Haase⁵ We hypothesize that antigen-specific CD8+ T cells down-modulate CD8 upon entering B-cell follicles or upon entering the epithelial layer of tissues in macaques, perhaps preventing unwanted cellular lysis and modulating immune activation in these specific tissue locations. Future studies are needed to determine whether this phenomenon also occurs during HIV and other infections.
97	MAINTENANCE OF HIV-SPECIFIC CD4+ T CELL HELP DISTINGUISHES HIV-2 FROM HIV-1 INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 97) Melody Duvall^1,2, A Jaye³, T Dong¹, J Brenchley², D Jeffries³, D Douek², A McMichael¹, H Whittle³, R Koup², and S Rowland-Jones^1,3 HIV-2-infected individuals with non-progressive disease mount a functionally superior HIV-specific CD4+ T cell response compared with HIV-1+ individuals or HIV-2+ progressors. This response is principally distinguished by a non-terminally differentiated, polyfunctional population of cytokine-producing cells with preserved proliferative capacity. In contrast to the diminished or absent HIV-1-specific CD4+ T cell response, a strong, functionally diverse, and heterogeneous HIV-2-specific CD4+ helper T cell response may be a contributing factor in the attenuated clinical phenotype of HIV-2 infection.
98	IMMUNE CONTROL OF HIV INFECTION: PREDICTABILITY IN THE MIDST OF CHAOS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 98) Bruce Walker Using transmission pairs to control for the infecting virus, acute infection to control for duration of infection, and large population studies to control for viral and host genetic heterogeneity, it is clear that there is considerable predictability in the virus–host interaction, and that there are constraints on viral evolution under immune selection pressure. Such studies indicate that adaptive immune responses vary in their antiviral efficacy, and suggest that it may be possible to develop immunogens that represent the predictable variants that will arise under immune selection pressure.
Session 23—Oral Abstracts Antiretroviral Therapy II: New Insights and Treatment Strategies
101	PREDICTORS OF HIV DISEASE PROGRESSION IN PATIENTS WHO STOP ART WITH CD4 CELL COUNTS >350 CELLS/mm³ Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 101) Daniel Skiest¹, D Havlir², R Coombs³, E Adams⁴, P Cain⁵, T Petersen⁶, D Rusin⁷, C Jennings⁸, K Robertson⁹, D Margolis⁹, and the ACTG 5170 Team ART interruption was generally safe in this cohort. Low nadir CD4 count is the best predictor of CD4 decline or clinical events following ART cessation.
102	CD4-GUIDED SCHEDULED TREATMENT INTERRUPTIONS COMPARED TO CONTINUOUS THERAPY: RESULTS OF THE STACCATO TRIAL Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 102) Jintanat Ananworanich¹, A Gayet-Ageron², M Le Braz², W Prasithsirikul³, P Chetchotisakd⁴, S Kiertiburanakul⁵, P Phanuphak¹, D Cooper⁶, K Ruxrungtham¹, B Hirschel², and the Staccato Study Group During 484 patient-years of STI, little evidence of treatment resistance emerged. Treatment-related adverse effects were more frequent in continuous therapy, but minor manifestations of HIV infection were more frequent in STI.
103	FINAL RESULTS OF A RANDOMIZED, CONTROLLED TRIAL OF STRUCTURED TREATMENT INTERRUPTIONS VS CONTINUOUS HAART IN CHRONIC HIV-INFECTED SUBJECTS WITH PERSISTENT SUPPRESSION OF VIRAL REPLICATION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 103) Lucia Palmisano, M Giuliano, R Bucciardini, M Andreotti, V Fragola, C Galluzzo, M Pirillo, M Mancini, L Weimer, S Vella, and the Italian ISS PART Clin Ctrs Potential candidates to structured treatment interruptions are subjects with high pre-HAART CD4 count, absence of archived mutations, and residual replication <2.5 copies HIV RNA/mL. For this therapeutic strategy NNRTI-based regimens appear preferable to unboosted PI HAART.
104	STRUCTURED TREATMENT INTERRUPTIONS IN HIV-INFECTED PATIENTS WITH HIGH CD4 CELL COUNTS AND VIROLOGIC SUPPRESSION: RESULTS OF A PROSPECTIVE, RANDOMIZED, OPEN-LABEL TRIAL (WINDOW - ANRS 106) Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 104) Bruno Marchou¹, P Tangre², I Charreau², J Izopet¹, P M Girard³, T May⁴, J M Ragnaud⁵, J P Aboulker², J M Molina⁶, and ANRS 106 Study Group In this population of patients, a fixed structured treatment interruption strategy of 8-weeks-off/8-weeks-on appeared clinically and immunologically safe over 96 weeks while sparing 48.5% of drug exposure. Patterns of drug resistance mutations in patients with virologic failure appeared similar.
105LB	THE CD4-GUIDED STRATEGY ARM STOPPED IN A RANDOMIZED STRUCTURED TREATMENT INTERRUPTION TRIAL IN WEST-AFRICAN ADULTS: ANRS 1269 TRIVACAN TRIAL Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 105LB) Christine Danel¹, R Moh¹, S Sorho¹, A Minga¹, A Anzian¹, O Ba-Gomis¹, D Gabillard², E Bissagnene¹, R Salamon², X Anglaret², and ANRS 1269 Study Group CGT led to a 2-fold higher serious morbidity rate than CT, mainly due to invasive bacterial diseases. Further structured treatment interruption trials assessing CGT strategies in sub-Saharan Africa should use higher CD4 thresholds for interruption/introduction. Whether a fixed treatment-interruption strategy is appropriate in Côte d’Ivoire requires further follow-up.
106LB	EPISODIC CD4-GUIDED USE OF ART IS INFERIOR TO CONTINUOUS THERAPY: RESULTS OF THE SMART STUDY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 106LB) Wafaa El-Sadr and J Neaton for the SMART Study Investigators SMART, a large international trial, demonstrated that CD4-guided episodic ART use aimed at maintaining CD4 >250 cells/mm³ is associated with increased short-term risk of progression of HIV disease and death compared to continuous ART.
107LB	EFFICACY AND SAFETY OF ATAZANAVIR-BASED THERAPY IN ANTIRETROVIRAL NAÏVE HIV-1 INFECTED SUBJECTS, BOTH WITH AND WITHOUT RITONAVIR: 48-WEEK RESULTS FROM AI424-089 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 107LB) Niel Malan¹, E Krantz², N David³, K Kastango⁴, D Frederick⁴, M Matthew⁴, S Schnittman⁴, J Hammond⁴, and the -089 Study Group In this study in ART-naïve HIV+subjects, ATV, with or without RTV, demonstrated a high rate of virologic response through 48 weeks. Both arms were generally safe and well tolerated, although subjects on ATV/r had a higher rate of hyperbilirubinemia. These results support additional studies using ATV/r in ART-naïve subjects.
108LB	A PROSPECTIVE, OPEN-LABEL, PILOT TRIAL OF REGIMEN SIMPLIFICATION TO ATAZANAVIR/RITONAVIR ALONE AS MAINTENANCE ANTIRETROVIRAL THERAPY AFTER SUSTAINED VIROLOGIC SUPPRESSION (ACTG 5201) Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 108LB) Susan Swindells¹, T Wilkin², G DiRienzo³, C Fletcher⁴, G Thal⁵, H Huang³, E Werner⁴, J McKinnon⁶, J Mellors⁶, and the AIDS Clin Trials Group Simplified maintenance therapy with ATV/RTV alone appears safe and effective through 24 weeks. Virologic failure occurred in 3 of 34 subjects, 2 of whom had undetectable plasma ATV concentrations. Resistance to PI was not detected at virologic failure. Larger, randomized trials are now warranted to define further the efficacy of this strategy.
109LB	SAFETY OF NEVIRAPINE COMPARED TO ABACAVIR ON A BACKGROUND OF ZIDOVUDINE/LAMIVUDINE AS FIRST-LINE ANTIRETROVIRAL THERAPY: A RANDOMIZED DOUBLE-BLIND TRIAL Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 109LB) Paula Munderi and the DART Trial Team Compared with NVP, ABC had a lower discontinuation rate and a trend toward a lower rate of serious adverse reactions in African patients initiating ART with low CD4 counts. With the possible exception of hepatotoxicity, there was considerable overlap in the clinical manifestations of reactions to ABC and NVP in this population.
110	VIRAL DECAY RATES IN MEN AND WOMEN RECEIVING TRIPLE-NUCLEOSIDE OR EFAVIRENZ-CONTAINING ART: VIRAL DYNAMICS SUBSTUDY OF ACTG A5095 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 110) Kathleen Squires¹, H Ribaudo², D Kuritzkes³, C Shikuma⁴, W Meyer⁵, K Klingman⁶, R Gulick⁷, and ACTG A5166s and ACTG A5095 First phase viral decay rates were significantly faster in patients receiving ZDV/3TC+EFV compared with a triple NRTI regimen; no other treatment differences in first or second phase viral decay rates were seen. There were no differences in viral decay rates between men and women.
Session 27—Symposium What's New in Vaccines: The Membrane Proximal Region of HIV Envelope and Its Role as a Target of Broadly Neutralizing Antibodies
111	IN VITRO AFFINITY MATURATION OF THE HIV-1 BROADLY NEUTRALIZING ANTI-gp41 ANTIBODY Z13 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 111) Michael Zwick, J Nelson, F Brunel, R Cardoso, I Wilson, P Dawson, and D Burton Our structure-function analysis of peptides specific for Z13e1 and 4E10 has provided new insights into the cognate epitopes on the MPER of gp41 and may be helpful in structure-based vaccine design. Finally, a whole IgG Z13e1 has been engineered and neutralization behavior and potential autoreactivity are being investigated.
112	POTENTIAL DIFFICULTIES IN ELICITING ANTIBODIES TO THE MEMBRANE PROXIMAL REGION OF HIV-1 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 112) Barton Haynes, L Verkoczy, A Moody, G Kelsoe, and A Alam These findings have raised the hypothesis that some species of broadly neutralizing antibodies may not be readily made because they are subjected to negative B cell immunoregulatory control. A related hypothesis proposes that animals or patients with defects in B cell tolerance under certain circumstances will be able to make 2F5 and 4E10-like antibodies that neutralize HIV-1. We will discuss strategies to test these hypotheses, and present data from studies in animals regarding analysis of origin of anti-MPER B cells.
113	THE MEMBRANE PROXIMAL EXTERNAL REGION OF HIV-1 ON DIFFERENT VIRAL SCAFFOLDS: DETECTION OF EPITOPE-SPECIFIC NEUTRALIZING ANTIBODIES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 113) F Bibollet-Ruche¹, J Decker^1,2, H Li¹, P Goepfert¹, M Peeters³, S Allen⁴, E Hunter⁴, J Robinson⁵, P Kwong⁶, and George M Shaw^1,2 These results indicate that the MPER of HIV-1 is inherently immunogenic and elicits neutralizing antibody responses in a substantial proportion of infected patients. Epitopes recognized by these neutralizing antibodies are distinct from those recognized by 4E10 or 2F5.
114	LESSONS FROM THE USE OF MEMBRANE PROXIMAL EXTERNAL REGION ANTIBODIES IN VIVO Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 114) Alexandra Trkola, A Manrique, P Rusert, B Joos, M Fischer, M Huber, H Kuster, and H Gunthard Viruses preserved sensitivity to the MPER monoclonal antibodies 2F5 and 4E10 in vivo despite the ability of the tested viral isolates to tolerate mutations in the epitope of these antibodies in vitro. Collectively these data suggest, that in vivo dosing or distribution of 2F5 and 4E10 to the relevant sites of viral replication was too low to exert immune selection or alternatively, that in vivo selection pressures against the generation of such mutants exist.
Session 28—Symposium Almost 20 Years of Antiretroviral Therapy: Still a Lot to Learn
115	IMPLICATIONS OF EARLY EVENTS IN HIV INFECTION FOR TREATMENT: BACK TO THE FUTURE? Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 115) Jeff Lifson While the potential benefits of effective, non-toxic treatment aggressively implemented during primary infection appear considerable, and such approaches should continue to be studied as new treatments are developed, experience with currently available drug regimens does not seem to support early treatment as a standard of care.
116	IS HIV A FEMINIST? SEX DIFFERENCES IN OUTCOMES ON HAART Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 116) Monica Gandhi Given the racial and ethnic mix of HIV among women in the United States, and the overwhelming burden of infection in specific regions around the globe, this variability needs further study in population pharmacokinetic models, especially those that incorporate pharmacogenomic parameters. Finally, psychosocial factors play a role in sex-based differences in the HAART era, including effects on adherence and access to therapy. This talk will summarize the studies to date that have examined sex disparities in outcomes on HAART over the last 10 years. The focus of this discussion will be entirely on sex differences in responses to ART and will not review the literature on sex disparities in HIV infection prior to the HAART era. Although a number of investigations have specifically looked at sex differences in outcomes on HAART, a number of opportunities have been missed to recruit more women into HIV clinical trials to stratify and analyze outcomes by sex. As we approach the 20-year mark for ART, we require a greater mandate to conduct studies on sex disparities in HAART outcomes to optimize therapy for an increasingly feminized epidemic.
117	LIMITING THE LIMITATIONS OF ANTIRETROVIRALS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 117) Andrew Carr This presentation will focus on the diagnosis and potential management strategies for these toxicities.
118	NEW AGENTS AND TREATMENT PARADIGMS: NAVIGATING THROUGH THE DRUG DEVELOPMENT MINE FIELD Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 118) Michael Saag This will review the process of drug discovery, illustrated with examples of exhilarating successes and disappointing failures, with a focus on the current status of new drug development and its potential impact on the future of clinical practice, including the cost of care, for HIV patients worldwide.
Session 31—Plenary
120	CIRCUMCISION AND HIV TRANSMISSION: THE CUTTING EDGE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 120) Thomas C Quinn These epidemiologic, biological, and clinical trial results provide strong evidence that male circumcision significantly lowers the risk of HIV acquisition. Mathematical models of implementing male circumcision in countries with high incident rates suggest marked reductions in HIV incidence in men with subsequent decreased transmission rates to women. Policy implications of recommending male circumcision to populations in high-risk countries need to take into consideration cultural norms, religious traditions, national and local laws. Circumcision may represent one important biological intervention to decreasing the acquisition of HIV, but will need to be carefully integrated into other HIV prevention and sexually transmitted disease control programs prevent subsequent behavioral disinhibition among circumcised men.
Session 32—Plenary
121	PREVENTING HIV TRANSMISSION BY TOPICAL MICROBICIDES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 121) John Moore A practical microbicide product must not only be effective, but must also be safe, affordable, and acceptable to the user. Some, or all, microbicides will have to overcome various obstacles if they are eventually to be developed as products for men and women to use.
Session 33—Oral Abstracts Mother-to-Child Transmission and HIV in Women
122LB	EVIDENCE FOR PERSISTENT, OCCULT INFECTION IN NEONATAL MACAQUES FOLLOWING PERINATAL TRANSMISSION OF SHIV-SF162P3 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 122LB) Nancy Haigwood^1,2, L Misher¹, C Ng², T Zhu², L Kuller³, P Polacino³, H Bielefelt-Ohmann³, D Mohan¹, S L Hu^2,3, and P Jayaraman^1,2 Mechanisms accounting for low-level viral persistence in these neonates are presently unclear. A minority of adults exposed repeatedly to HIV can remain seronegative; in some cases these exposed seronegative individuals have HIV-1 DNA persisting in resting CD4+ T cells at levels below the detection limit of conventional PCR assays. Maternal IgG could contribute to rapid viral control, although at least some of the infant transmitted envs in pseudotyped virus are resistant to maternal neutralizing antibodies. Understanding the control of SHIV infection in newborn macaques at such low levels has implications for lentiviral pathogenesis and potential vaccine strategies to limit breast-milk transmission.
123	IDENTIFICATION OF A HUMAN MILK GLYCOPROTEIN THAT BINDS DC-SIGN AND INHIBITS HIV-1 TRANSFER TO CD+ T LYMPHOCYTES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 23) Marloes Naarding¹, A Dirac², D Speijer¹, G Pollakis¹, and W Paxton¹ We have identified a specific glycoprotein in human milk that binds to DC-SIGN and can inhibit HIV-1 transfer to CD4+ T lymphocytes. Identification of this molecule may provide for a better understanding of mother-to-child transmission of HIV-1 via breastfeeding and provide a further target for future microbicide development.
124	EVIDENCE FOR DISTINCT MECHANISMS FOR INTRAUTERINE AND INTRAPARTUM HIV MOTHER-TO-CHILD TRANSMISSION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 124) Elizabeth Russell¹, J Kwiek¹, V Mwapasa², M Malyneux³, S Rogerson⁴, R Swanstrom⁵, and S Meshnick¹ Intrauterine and intrapartum appear to represent distinct mechanisms of transmission. Intrauterine transmission represents a greater bottleneck but involves transmission of the predominantly circulating virus. Intrapartum transmission represents less of a bottleneck but often involves the transmission of rare variants that are either compartmentalized in the mother or highly selected.
125	EFFECTIVENESS OF REPEAT SINGLE-DOSE NEVIRAPINE IN SUBSEQUENT PREGNANCIES AMONG UGANDAN WOMEN Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 125) C Eure¹, Paul Bakaki², M McConnell¹, M Mubiru², M Thigpen¹, P Musoke², F Mmiro², M Fowler², and the MUJHU NVP Resistance Group Based on both retrospective and prospective data including women from the HIVNET 012 trial, no increased risk of infant HIV infection was noted in subsequent pregnancies for Ugandan women with prior sdNPV exposure compared to NVP-naïve women.
126	COTRIMOXAZOLE PROPHYLAXIS AND ADVERSE BIRTH OUTCOMES AMONG HIV-INFECTED WOMEN IN LUSAKA, ZAMBIA Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 126) Jan Walter¹, M Mwiya², N Scott³, P Kasonde², M Sinkala⁴, C Kankasa², S Kauchali¹, G Aldrovandi⁵, D Thea³, and L Kuhn¹ We observed reductions in chorioamnionits, prematurity, and neonatal mortality after the introduction of routine cotrimoxazole prophylaxis for HIV-infected women with CD4 cell counts <200. These data suggest that this intervention may have indirect benefits for neonatal and infant health in addition to its direct benefits for maternal health.
127	RAPID HIV TESTING AND PREVENTION OF MOTHER-TO-CHILD HIV TRANSMISSION IN HIGH-RISK MATERNITY HOSPITALS, ST PETERSBURG, RUSSIA, 2004-2005 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 127) Dmitry Kissin¹, N Akatova², A Rakhmanova³, E Vinogradova⁴, E Voronin⁵, D Jamieson¹, M Glynn¹, J Robinson⁶, W Miller⁷, S Hillis¹, and PMTCT in High-Risk Women Project Team The use of RT achieves timely detection of HIV-infected women presenting in labor with undocumented HIV status, and facilitates appropriate delivery of intrapartum ART prophylaxis to these women and their infants. The success of PMTCT program could be improved by: strengthening programs emphasizing the importance of early presentation for labor and delivery; identifying timely and efficient confirmatory algorithm for RT; improving follow-up for perinatally exposed infants; strengthening prevention of unintended pregnancy in HIV-infected women; and intensifying interventions to prevent infant abandonment.
128	MALE CIRCUMCISION AND THE RISKS OF FEMALE HIV AND SEXUALLY TRANSMITTED INFECTIONS ACQUISITION IN RAKAI, UGANDA Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 128) R Gray¹, M Wawer², M Thoma¹, D Serwadda³, F Nalugoda⁴, X Li¹, G Kigozi⁴, N Kiwanuka⁴, O Laeyendecker⁵, and Thomas C Quinn⁵ In these observational data, male circumcision was associated with reduced risk of female HIV acquisition and lower risks of selected sexually transmitted infections. Circumcision may affect male HIV infectivity by removal of the foreskin mucosa thus reducing female HIV exposure, and/or an indirect effect via reduction of female sexually transmitted co-infections and genital ulcer disease. Depending on the results of an on ongoing randomized trial, male circumcision may have an important role for HIV and sexually transmitted infections prevention in women.
129	FIRST DOSE AND STEADY-STATE GENITAL TRACT PHARMACOKINETICS OF TEN ANTIRETROVIRAL DRUGS IN HIV-INFECTED WOMEN: IMPLICATIONS FOR PRE- AND POST-EXPOSURE PROPHYLAXIS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 129) Julie Dumond, R Yeh, K Patterson, A Corbett, B H Jung, N Rezk, A Bridges, E Dempsey, M Cohen, and A Kashuba Understanding exposure profiles for ARVs in the GT is particularly important for PREP, PEP, and possibly the prevention of mother-to-child-transmission. ZDV, 3TC, and FTC achieve GT exposures greater than that of BP. Since standard BP CONC for these agents have demonstrated virologic efficacy, it would be expected that the higher GT CONC would make these excellent candidates for PREP/PEP regimens. ATV and ddI achieve moderate GT CONC and may also prove useful in these regimens (ATV in particular with a low IC₅₀ for HIV^WT). ARVs achieving <10% of BP exposure in the GT (d4T, LPV, EFV) may be less optimal candidates.
130	INITIATION OF ART LEADS TO A RAPID DECLINE IN CERVICAL AND VAGINAL HIV-1 RNA Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 130) Susan Graham¹, S Holte², B Richardson¹, D Panteleeff², W Jaoko³, J Ndinya-Achola³, N Peshu⁴, K Mandaliya⁵, J Overbaugh², and R McClelland¹ Genital HIV-1 RNA shedding decreased rapidly after ART initiation, but 7 of 20 women had detectable genital HIV-1 shedding after 1 month of ART. These findings are consistent with a rapid decrease in infectivity. However, persistent genital HIV-1 shedding may indicate an ongoing risk of transmission by some women.
131	INFECTION WITH TRICHOMONAS VAGINALIS INCREASES THE RISK FOR HIV-1 ACQUISITION: A PROSPECTIVE STUDY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 131) R Scott McClelland^1,2, L Lavreys^1,2, W Hassan^1,2, K Mandaliya³, J Kiarie², J Ndinya-Achola², W Jaoko², and J Baeten¹ In this large, prospective cohort study, T. vaginalis infection was associated with a significant increase in the risk of HIV-1 acquisition. Given the high global prevalence of trichomoniasis, this infection could account for a high population attributable risk percentage for HIV-1 acquisition. Interventions to reduce the prevalence of T. vaginalis infection should be evaluated as a potentially important HIV-1 prevention strategy.
Session 34—Oral Abstracts HIV-1 Origins, Viral Infection and Cellular Co-Factors
132	NATURAL RESERVOIRS OF CHIMPANZEE LENTIVIRUSES CLOSELY RELATED TO HIV-1 GROUPS M AND N Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 132) Fran Van Heuverswyn¹, F Liegeois¹, S Loul², C Neel^1,2, B Keele³, Y Li³, B Hahn³, E Mpoudi-Ngolle², E Delaporte¹, and M Peeters¹ These findings confirm the widespread and longstanding presence of natural SIV_cpz variants closely related to group M and N in wild chimpanzee populations of the Pan troglodytes troglodytes subpecies in Cameroon. These observations provide additional insights in the origin of the HIV-1 epidemic in central Africa.
133	LANGERHANS CELLS MEDIATE HIV TRANS-INFECTION OF TARGET CELLS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 133) Kelly Fahrbach, S Barry, and T Hope We find that activated LC can mediate trans-infection. Furthermore, we find a dramatic difference in the trafficking of HIV in activated LC. Together, these observations reveal that LC have the potential to play a role in sexual transmission via trans-infection of HIV, especially under conditions of inflammatory responses known to increase the efficiency of sexual transmission.
134	NON-MACROPHAGE-TROPIC R5 ENVELOPES PREDOMINATE IN BLOOD, LYMPH NODE, AND SEMEN: IMPLICATIONS FOR TRANSMISSION AND PATHOGENESIS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 134) P Peters¹, M Sullivan¹, M Duenas Decamp¹, J Bhattacharya¹, K Luzuriaga¹, J Bell², P Simmonds², J Ball³, and Paul Clapham¹ The lack of macrophage-tropism for the majority of the envelopes amplified from lymph node, blood, and semen is striking and contrasts with the current consensus that R5 primary isolates are generally macrophage-tropic. The extensive variation in R5 tropism reported here is likely to have an important influence on pathogenesis and on the capacity of HIV-1 to transmit.
135	MUTATION OF HIV-1 GAG RELIEVES THE EARLY, POSTENTRY BLOCK BY PRE-mRNA FACTOR CPSF6 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 135) Zandrea Ambrose¹, T Martin¹, K Lee¹, J Baumann¹, I Taniuchi², J Julias^1,3, T Takemura¹, D Unutmaz⁴, S Hughes¹, and V Kewalramani¹ These data highlight the role of Gag in determining retroviral susceptibility to early, antiviral factors. Examining the uncoating and trafficking of HIV-1 that is resistant to truncated CPSF6 will help elucidate the restriction mechanism and may identify cellular machinery intrinsic to primate lentiviral replication.
136	SELECTIVE DESTRUCTION OF THE HIV-1 CAPSID SHELL BY THE RESTRICTION FACTOR TRIM5 α Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 136) U Chatterji and Philippe Gallay By demonstrating that TRIM5α and TRIM5-CypA block HIV-1 by surgically destroying the capsid shell that surrounds the viral genome, our study sheds light on the mechanisms of anti-viral action of TRIM5α proteins. This is the first proof that capsid is the direct target for TRIM5 attack and that capsid destruction alone suffices to arrest HIV-1. Although TRIM5α contains a ubiquitin ligase domain, the TRIM5-mediated proteolytic attack of capsid is apparently independent of the proteasome. This is the first demonstration of a direct relationship between TRIM5-mediated restriction in HIV-1 replication, and specific capsid degradation. The findings imply more than a simple structural role for capsid after virus enters the cell and offer another target for development of useful interventions. This also provides the first hint of how TRIM5 limits zoonotic retroviral transmission among mammalians.
137	MULTIPLE CYTOPLASMIC HUMAN TRIPARTITE MOTIF PROTEINS BLOCK HIV REPLICATION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 137) D Marchant¹, S Neil¹, G Carter¹, I Harrison¹, K Aubin¹, G Meroni², and Aine McKnight¹ After fusion with the cell membrane and entry into the cytoplasm, HIV-1 and -2 must therefore avoid host intracellular anti-viral factors including TRIM 1, 18, and 34 to complete replication. It will be important to determine the role of these TRIM proteins in the tissue compartmentalisation and pathogenesis of HIV.
138	MULTIPLE APOBEC3 FAMILY CYTIDINE DEAMINASES ARE POTENT INHIBITORS OF MAMMALIAN RETROTRANSPOSONS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 138) Hui Chen, Q Yu, J Chou, E Francisco, and N Landau The results further support a role for APOBEC cytidine deaminases in the inhibition of the endogenous retrotransposons. APOBEC3A is a potent inhibitor, which may be attributable to its cellular localization, small size, and potent cytidine deaminase activity.
139	REGULATED FORMATION OF HIV-1 Vif-Cul5 E3 UBIQUITIN LIGASE THROUGH A NOVEL ZINC-BINDING DOMAIN-STABILIZED HYDROPHOBIC INTERFACE IN Vif Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 139) Elana Ehrlich¹, Z Xiao^1,2, K Luo^1,2, T Wang¹, C Tian¹, Y Yu¹, and X F Yu^1,2 The distinct zinc-binding motif used by HIV and SIV Vif, but not cellular proteins, to assemble with Cul5-E3 raises an interesting question as to the origin of Vif molecules and may represent a target for the development of novel therapeutics.
140LB	OVER-EXPRESSION OF THE LEDGF/p75 INTEGRASE BINDING DOMAIN ABROGATES HIV-1 REPLICATION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 140LB) Zeger Debyser, L Vandekerkchove, J Derijck, R Gijsbers, M Witvrouw, and F Christ The highly potent inhibition of HIV-1 replication in cell lines over-expressing the IBD of LEDGF/p75 settles the debate about the importance of LEDGF/p75 for viral replication and provides a proof-of-principle for a novel antiviral therapeutic strategy targeting the interaction of LEDGF/p75 with HIV-1 IN. By binding to HIV-1 IN, the IBD likely competes with the binding of native LEDGF/p75 that is required to dock the preintegration complex to the chromosomes.
141LB	BALANCING SELECTION, GENE DUPLICATION AND FUNCTIONAL POLYMORPHISM IN THE RHESUS MACAQUE AND SOOTY MANGABEY TRIM5α LOCUS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 141LB) R Newman, L Hall, M Connole, G L Chen, A Kaur, G Miller, and Welkin Johnson Together, these features are strong evidence for ongoing, balancing selection operating on the TRIM5 locus, and imply that TRIM5α may act as an innate defense against multiple pathogens. Our analysis suggests that interspecies diversity is largely a reflection of within-species variation. These results are in striking contrast to the finding that human TRIM5 is relatively monomorphic. We propose that polymorphic sites define residues involved in target recognition, consistent with reports that these same regions influence specificity in tissue culture assays. Our findings have relevance to nonhuman primate models of disease, and indicate that generalized conclusions regarding species-specificity of TRIM5α should not be based on the analysis of 1e or even a few clones per species.
Session 35—Oral Abstracts Complications of Antiretroviral Therapy and HIV
142	EARLY CLINICAL TOXICITY TO NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR-BASED HAART IN A HOME-BASED AIDS CARE PROGRAM IN RURAL UGANDA Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 142) Fatu Forna¹, C Liechty², P Solberg², F Asiimwe², W Were², J Mermin², P Behumbiize², T Tong¹, J Brooks¹, and P Weidle¹ Clinically apparent toxicities were common, but the probability of severe clinical toxicity was moderate. Neuropathy and rash accounted for most events, and required single drug substitutions in many cases. In resource-limited settings, ART intolerance to a regimen containing d4T and NVP presents a manageable barrier to care, though more tolerable regimens would be desirable.
143	ADVERSE EVENTS IN HIV-INFECTED PATIENTS RECEIVING ART IN A TREATMENT PROGRAM IN A NAIROBI SLUM, KENYA, 2003 TO 2005 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 143) A Kim¹, L Ngan’ga², D Macharia², M Wangai³, F Ilako⁴, A Isavwa², B Marston², Kevin M Decock², and P Weidle¹ Toxicities were common in this cohort, but most were mild. Although some patients had severe toxicities, ART was continued with an alternative regimen. These results indicate that among populations in resource-limited settings, ART tolerance should not represent a significant barrier to care.
144	EXPOSURE TO PI AND NNRTI AND RISK OF MYOCARDIAL INFARCTION: RESULTS FROM THE D:A:D STUDY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 144) Nina Friis-Møller¹, P Reiss², W El-Sadr³, A D'Arminio Monforte⁴, R Thiébaut⁵, S De Wit⁶, R Weber⁷, E Fontas⁸, M Law⁹, A Phillips¹⁰, and and the D:A:D Study Group Increased PI exposure is associated with an increased risk of MI, which is partly explained by dyslipidemia. Conversely, although there were fewer years of experience, we found no evidence that increased NNRTI exposure is associated with risk of MI.
145	3-YEAR FOLLOW-UP OF CAROTID INTIMA-MEDIA THICKNESS IN HIV-INFECTED AND UNINFECTED ADULTS: ACTG 5078 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 145) Judith Currier¹, M Kendall², K Henry³, F Torriani⁴, J Conley⁵, B Alston-Smith⁶, M Basar⁷, K Mickelberg⁸, Y Li9, H Howard⁹, and ACTG 5078 Study Team In this analysis, matching for known coronary heart disease (CHD) risk factors, neither HIV infection nor PI exposure significantly affected the rate of progression of carotid IMT over 3 years of follow-up. These results suggest that “classic” CHD factors may play a more significant role than ART in the increased incidence of cardiovascular events observed in HIV-infected individuals.
146	THE SAFETY AND EFFICACY OF FISH OIL IN COMBINATION WITH FENOFIBRATE IN SUBJECTS ON ART WITH HYPERTRIGLYCERIDEMIA WHO HAD AN INCOMPLETE RESPONSE TO EITHER AGENT ALONE: RESULTS OF ACTG A5186 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 146) John Gerber¹, D Kitch², J Aberg³, R Zackin², S Charles⁴, E Hogg⁵, E Acosta⁶, E Connick¹, D Wohl⁷, C Fichtenbaum⁸, and ACTG A5186 Team Fish oil is an effective and safe agent in the treatment of ART-associated HTG even though the majority of subjects did not reach serum TG ≤200 mg/dL. When fish oil is combined with fenofibrate, further TG lowering is observed.
147	EFFECTS OF METFORMIN AND ROSIGLITAZONE ON BODY COMPOSITION IN HIV-INFECTED PATIENTS WITH HYPERINSULINEMIA AND ELEVATED WAIST/HIP RATIO: A RANDOMIZED, PLACEBO-CONTROLLED TRIAL Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 147) Kathleen Mulligan^1,2, Y Yang³, S Koletar⁴, D Wininger⁴, R Parker³, B Alston-Smith⁵, M Basar⁶, S Grinspoon^7,8, and ACTG Protocol 5082 Team Neither rosiglitazone alone, metformin alone, nor the combination significantly changed abdominal visceral or subcutaneous adipose tissue over 16 weeks, but significant dose reductions and discontinuations in the metformin arm may have affected these results. Rosiglitazone increased lower extremity fat compared to placebo.
148	A RANDOMIZED PLACEBO-CONTROLLED TRIAL OF METFORMIN FOR THE TREATMENT OF HIV LIPODYSTROPHY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 148) Rakhi Kohli, C Wanke, S Gorbach, and A Shevitz This randomized placebo-controlled trial failed to show a benefit of metformin on fat redistribution or dyslipidemia in HIV-infected persons with lipodystrophy and normal glucose tolerance. There was an unexpected trend toward reduction in appendicular fat mass. Metformin should be used with caution in HIV-associated lipodystrophy, and if used, should be reserved for persons with impaired glucose tolerance.
149	EFFECTS OF PHYSIOLOGIC TESTOSTERONE SUPPLEMENTATION ON FAT MASS AND DISTRIBUTION IN HIV-INFECTED MEN WITH ABDOMINAL OBESITY: ACTG 5079 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 149) Cecilia Shikuma¹, R Parker², F Sattler³, B Alston⁴, R Haubrich⁵, T Umbleja², S Bhasin⁶, and AIDS Clin Trials Group Protocol A5079 Study Team Testosterone replacement in HIV+ men with abdominal obesity and low testosterone levels was associated with a decrease in whole body and abdominal subcutaneous fat content and with an increase in lean mass compared to placebo; changes in visceral fat mass were not significantly different between the 2 groups. Further studies are needed to examine testosterone’s effects on insulin sensitivity, lipids, and atherosclerosis progression.
150	RANDOMIZED, PLACEBO CONTROLLED TRIAL OF VALGANCICLOVIR TO PREVENT CMV END-ORGAN DISEASE AMONG HIV-INFECTED SUBJECTS WITH DETECTABLE PLASMA CMV DNA PCR: ACTG 5030 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 150) David Wohl¹, M Kendall², J Andersen², C Crumpacker³, S Spector⁴, J Feinberg⁵, B Alston-Smith⁶, S Owens⁷, S Chafey⁸, and M Jacobson⁹ Although studies in the pre-HAART era reported that >50% of patients with CD4 <50 cells/mm³ and CMV viremia developed CMV end-organ disease, we observed a much lower CMV end-organ disease rate among such patients in the HAART era, but did observe a high rate of mortality in this cohort. Our findings indicate that pre-emptive anti-CMV does not significantly reduce the risk of CMV end-organ disease or of death in subjects receiving HAART.
151LB	EFFECT OF PIOGLITAZONE ON HIV-1 RELATED LIPOATROPHY: A RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED TRIAL (ANRS 113) WITH 130 PATIENTS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 151LB) L Slama¹, E Lanoy², M A Valentin^2,3, J P Bastard^1,4, A Chermak², A Boutekatjirt³, D William-Faltaos³, J Capeau^1,4, D Costagliola², and Willy Rozenbaum^1,5 PIO 30 mg once daily for 48 weeks improved limb lipoatrophy in antiretroviral-treated HIV-1-infected patients. This effect was not seen in patients exposed to d4T. PIO did not alter lipid parameters except for HDL cholesterol that was increased by PIO. These results support the use of PIO for the treatment of HIV-related lipoatrophy.
Session 36—Oral Abstracts HIV Drug Resistance: Mechanisms and Impact on Response to New Agents
152	MOLECULAR MECHANISM OF TENOFOVIR, ABACAVIR, AND LAMIVUDINE RESISTANCE BY THE K70E MUTATION IN HIV-1 REVERSE TRANSCRIPTASE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 152) Nicolas Sluis-Cremer, P Argoti Torres, J Grzybowski, U Parikh, and J Mellors The K70E mutation in HIV-1 RT confers resistance to NRTI via a nucleotide discrimination phenotype. The K70E mutation also significantly impairs the enzyme´s ability to excise AZT-MP, suggesting that this mutation may be antagonistic toward thymidine analog mutations. Therefore, the recent emergence of K70E in TDF-containing triple NRTI regimens might be counteracted by the addition of AZT.
153	CLONAL ANALYSIS OF HIV-1 QUASI-SPECIES ENABLES UNAMBIGUOUS IDENTIFICATION OF THE GENETIC DETERMINANTS OF VARIOUS PHENOTYPIC PROPERTIES OF THE ENVELOPE PROTEINS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 153) Jonathan Toma, W Huang, T Wrin, S Fransen, J Whitcomb, and C Petropoulos Clonal analyses of individual virus populations using high throughput assay systems enables identification of distinct changes in env that confer alterations in phenotype. These observations are consistent with a structurally integrated model of the gp120-gp41 glycoprotein complex. Application of this approach to additional virus populations will be used to extend our appreciation of envelope structure-function relationships that can be applied to the development of entry inhibitors and vaccines.
154	EFFECT OF BASELINE RESISTANCE ON THE VIROLOGIC RESPONSE TO A NOVEL NNRTI, TMC125, IN PATIENTS WITH EXTENSIVE NNRTI AND PI RESISTANCE: ANALYSIS OF STUDY TMC125-C223 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 154) Johan Vingerhoets¹, M Peeters¹, C Corbett¹, K Iveson², K Vandermeulen¹, R Keen², B Woodfall¹, and M P De Béthune¹ In this study of patients with extensive NNRTI and PI resistance, a viral load reduction of ≥1 log was observed at 24 weeks in patients using TMC125 with ≤2 NNRTI mutations. Patients with ≥3 mutations achieved a mean 0.66 log reduction, which while lower than the overall response to TMC125 (–1.18), was substantially higher than in the active control group (–0.19). This analysis shows that TMC125 retains activity in the presence of multiple NNRTI mutations where current NNRTI are not expected to be effective.
155	DISTINCT PATTERNS OF SEQUENCE VARIATION IN HIV-1 PRO AND POL IN CHRONICALLY INFECTED ART-NAÏVE INDIVIDUALS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 155) Frank Maldarelli¹, M Kearney¹, S Palmer¹, S Thawani¹, J Mican², D Rock², C Rehm², J Mellors³, and J Coffin¹ In contrast to HIV-1 samples taken from patients early in infection, sequence diversity in pro and pol is comparable and stable over time in chronically infected individuals. Position-specific analysis reveals that pro diversity is localized to specific regions. The presence of frequent recombination provides a potent mechanism for independent pro and pol variation.
156	VIRAL RESISTANCE TO PA-457, A NOVEL INHIBITOR OF HIV-1 MATURATION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 156) Catherine Adamson¹, K Salzwedel², A Castillo², R Goila-Gaur¹, S Ablan¹, J Doto², F Li², D Martin², C Wild², and E Freed¹ The clustering of PA-457-resistance-conferring mutations at the CA/SP1 junction confirms that this region is the major target of PA-457 activity. The drug dependence observed for A3V suggests multiple distinct mechanisms of resistance. Resistance to PA-457 was not detected in vivo during a 10-day, multi-dose study using standard genotyping methods. Interestingly, all the amino acid positions to which PA-457 resistance maps in vitro are highly conserved among HIV-1 isolates, suggesting that there may be a fitness cost to PA-457 resistance.
157	EFFECT OF BASELINE SUSCEPTIBILITY AND ON-TREATMENT MUTATIONS ON TMC114 AND CONTROL PI EFFICACY: PRELIMINARY ANALYSIS OF DATA FROM PI-EXPERIENCED PATIENTS FROM POWER 1 AND POWER 2 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 157) Sandra De Meyer¹, A Hill², I De Baere¹, L Rimsky¹, H Azijn¹, B Van Baelen¹, E De Paepe¹, T Vangeneugden¹, E Lefebvre³, and M P De Béthune¹ TMC114/r 600/100 mg twice daily showed significant efficacy benefits over CPI, independent of baseline CPI susceptibility. In a background of a substantial number of PI-resistance mutations, particular additional mutations may be associated with reduced TMC114 susceptibility.
158LB	IN VITRO CHARACTERIZATION OF HIV ISOLATED FROM PATIENTS TREATED WITH THE ENTRY INHIBITOR TNX-355 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 158LB) Thomas Duensing, M Fung, S Lewis, and S Weinheimer Baseline susceptibility to TNX-355 was independent of chemokine coreceptor tropism. In this investigation, HIV-1 subtype B viruses were susceptible at baseline. Further studies to correlate baseline susceptibility with virologic outcome and establish clinical cutoffs are needed.
159LB	POTENT ANTIRETROVIRAL EFFECT OF MK-0518, A NOVEL HIV-1 INTEGRASE INHIBITOR, IN PATIENTS WITH TRIPLE-CLASS RESISTANT VIRUS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 159LB) Beatriz Grinsztejn¹, B Y Nguyen², C Katlama³, J Gatell⁴, A Lazzarin⁵, D Vittecoq⁶, C Gonzalez⁷, J Chen², R Isaacs², and the Protocol 005 Study Team In this preliminary analysis of patients failing current therapies and with triple-class resistant virus, the HIV-1 integrase inhibitor, MK-0518 at all doses in combination with OBT had potent antiretroviral activity and was generally well-tolerated.
160LB	THE HIV INTEGRASE INHIBITOR GS-9137 (JTK-303) EXHIBITS POTENT ANTIVIRAL ACTIVITY IN TREATMENT-NAÏVE AND EXPERIENCED PATIENTS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 160LB) Edwin DeJesus¹, D Berger², M Markowitz³, C Cohen⁴, T Hawkins⁵, P Ruane⁶, R Elion⁷, C Farthing⁸, A Cheng⁹, B Kearney⁹, and 183-0101 Study Team GS-9137 monotherapy demonstrated substantial antiviral activity. Once-daily dosing of GS-9137 + RTV will be evaluated in a dose-ranging phase 2 study in treatment-experienced patients.
161LB	LATE VIROLOGIC BREAKTHROUGH IN TREATMENT-NAÏVE PATIENTS ON A REGIMEN OF COMBIVIR + VICRIVIROC Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 161LB) Wayne Greaves¹, R Landovitz¹, G Fatkenheuer², C Hoffmann³, F Antunes⁴, J Angel⁵, N Boparai¹, D Knepp¹, A Keung¹, and L Dunkle¹ Despite excellent tolerability and potent antiviral activity in vitro, in phase I studies, and at 14 days in this study, vicriviroc in combination with CBV did not provide durable suppression of plasma HIV RNA. Detailed analyses from this and ongoing studies are continuing to determine the role of selective entry inhibitors in potent antiviral therapy regimens.
Session 40—Symposium Public Health Strategies and Harm Reduction for HIV Prevention
162	QUANTIFYING THE IMPACT OF PRIMARY INFECTION ON HIV TRANSMISSION AND CONTROL Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 162) Christophe Fraser, T Hollingsworth, R Chapman, and R Anderson Within the context of a generalized epidemic, ART may have a large effect in reducing onward transmission even if given after primary infection, but before pre-AIDS/AIDS. The transmission of drug resistant strains during the infectious pre-AIDS/AIDS stage may however be a major problem which would only become apparent very gradually, but key parameters relating to transmission fitness of resistant strains upon which this depends have not yet been adequately measured.
163	HIV SEROSORTING AMONG MEN WHO HAVE SEX WITH MEN: IMPLICATIONS FOR PREVENTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 163) Matthew Golden Serosorting is common and provides substantial, but imperfect, protection against HIV. Efforts to increase serosorting, particularly if coupled with efforts to increase the frequency of HIV testing, would probably decrease HIV transmission as long as they were not associated with substantial increases in overall unprotected sex.
164	NORMALIZING HIV TESTING IN HEALTH CARE SETTINGS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 164) Timothy Mastro Promoting routine HIV testing in medical settings is a key strategy of CDC’s initiative, Advancing HIV Prevention: New Strategies for a Changing Epidemic, launched in 2003. CDC is in the process of revising recommendations for HIV testing in health care settings, with a goal of increasing the proportion of HIV-infected Americans who know their infection status to allow for linkage to prevention, care, and treatment services. Consideration is being given to recommending routine HIV screening in various health care settings based on cost-effectiveness analyses of different scenarios (including varying HIV prevalence), periodic rescreening for individuals with various risk indications, the type of counseling associated with testing in health care settings, the voluntary “opt-out” consent procedure for HIV testing as part of the consent for general care, and enhancing linkages to care and treatment. Expanded rescreening in the third trimester for women found to be HIV-negative early in pregnancy is also under consideration. CDC expects to issue revised recommendations in 2006.
165	PREVENTION IN HIV CLINICAL SETTINGS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 165) Jean L Richardson At baseline, unprotected anal or vaginal sex was less frequent for those with 1 partner (26%) than for those with 2 or more partners (50%). At posttest, among participants who had 2 or more sex partners at baseline, unprotected anal or vaginal sex was reduced 38% (p <0.001) among those who received the loss-frame intervention emphasizing negative consequences of unsafe sex. Unprotected anal or vaginal sex at follow-up was significantly lower in the loss-frame arm (OR = 0.42; 95%CI = 0.19 to 0.91, p = 0.03) compared with the control arm. No effects were seen in participants with only 1 partner or only a main partner at baseline. No significant changes were seen in the gain-frame arm. Studies that tested similar interventions will also be reviewed and suggestions for future intervention strategies will be discussed.
Session 41—Symposium Viral Reservoirs: Impact of Therapy
166	AFTER THE ACUTE PHASE: INFECTION AND DEPLETION IN TREATED AND UNTREATED CHRONIC HIV INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 166) Daniel Douek Here, we consider models of HIV disease pathogenesis in light of these findings and investigate their consequences during the chronic phase of infection with particular emphasis on persistent infection and depletion of CD4 T cells.
167	PERSISTENCE OF SIV IN THE INTESTINE OF TREATED OR IMMUNIZED MACAQUES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 167) Ronald Veazey In summary, the intestine is a major reservoir for HIV infection, regardless of whether patients are receiving ART. Evidence indicates that virus is continually replicating and eliminating CD4+ T cells in the intestine, even in patients in which plasma viral loads are effectively controlled. Treatment and vaccine strategies should target the intestine and stimulate mucosal immune responses, respectively.
168	HIV RESERVOIRS IN THE ERA OF EFFECTIVE ANTIVIRAL THERAPY: PERSPECTIVES FOR ERADICATION AND NEW THERAPEUTIC STRATEGIES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 168) Tae-Wook Chun These distinctions between early and delayed initiation of ART and the prospect of complete eradication of HIV in certain individuals need to be more fully explored as they may shed light on the immunologic and virologic factors involved in efficient clearance of HIV.
169	LONG-TERM PERSISTENCE OF LOW-LEVEL HIV-1 IN PATIENTS ON SUPPRESSIVE ANTIRETROVIRAL THERAPY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 169) John Coffin¹, F Maldarelli¹, S Palmer¹, A Weigand¹, S Brun², D Kempf², M King², G Hanna², and J Mellors³ These results imply that differences in regimen potency may not be due to differential ability to inhibit virus replication, but rather to either the frequency of resistant mutants in the virus population prior to therapy or to pharmacological or adherence issues. They also imply that the residual viremia is not due to ongoing replication of the virus, but rather release of virions from cells infected prior to therapy. Implications of these results for HIV pathogenesis and therapy will be discussed.
Session 42—Symposium Advances in the Understanding of HCV Biology and Treatment
170	HEPATITIS C VIRUS: A WILY AND REDOUBTABLE FOE AS THE HIV Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 170) T Jake Liang The ineffective and feeble immune response during chronic infection is probably the cause of continuous liver injury. Understanding the fundamental mechanisms of viral clearance, persistence, and hepatocellular injury is the key to developing effective vaccine and novel therapeutic strategies.
171	CURRENT CHALLENGES IN THE CLINICAL MANAGEMENT OF HIV/HCV CO-INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 171) Stuart Ray Therefore, greater understanding of disease pathogenesis and new therapeutic options are needed to address this increasingly important HIV-related condition.
172	HCV PROTEASE INHIBITORS: ACTIVITY AND RESISTANCE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 172) Ann Kwong BILN 2061 was developed by Boeringher Ingelheim and was the first HCV protease inhibitor (PI) to demonstrate proof-of-concept antiviral activity in hepatitis C patients. VX-950 and SCH 5030304 are small molecule inhibitors of the HCV NS3•4A serine protease, which have recently shown rapid and dramatic decreases in HCV RNA in the clinic and are being developed by Vertex Pharmaceuticals, Inc. and Schering-Plough, respectively. The clinical data for all 3 PI will be reviewed. In addition, resistance mutations observed in an in vitro cell-based system or in the clinic will be reviewed.
173	HCV POLYMERASE INHIBITORS: MULTIPLE SHOTS ON GOAL? Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 173) Daria Hazuda This presentation will review the HCV polymerase inhibitor field and discuss the challenges of assessing both preexisting resistance and resistance development for different classes of polymerase inhibitors in drug discovery and development.
Session 43—Oral Abstracts and Research Overview HIV Vaccines and Immune Based Therapies
174	EFFICACY OF A MULTIGENIC DNA/MVA VACCINE TO INDUCE MUCOSAL IMMUNE RESPONSES AND PROTECT AGAINST REPEATED LOW-DOSE VAGINAL SIV CHALLENGE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 174) Marie-Claire Gauduin¹, A Carville¹, P Kozlowski², M Piatak³, B Felber³, G Pavlakis³, G Mazzara⁴, J Lifson³, C Miller⁵, and R Johnson¹ Our results demonstrate the ability of a multigenic DNA/MVA prime/boost vaccine to induce CD8+ T cell responses in rectal and vaginal tissues and provide substantial reduction in viremia after repeated low dose vaginal challenge.
175	HEPATITIS B SURFACE ANTIGEN PARTICLES POSSESSING THE HIV-1 gp41 MEMBRANE PROXIMAL REGION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 175) Sanjay Phogat¹, B Welcher¹, J Muller², M Connors³, J Mascola¹, I Berkower², and R Wyatt¹ We have characterized novel HepB-MPR immunogens to potentially elicit antibodies against the gp41 MPR region. Immunogenicity studies using these particles themselves and in prime boost combination with gp160 proteoliposomes displaying the MPR in a native context are ongoing. We show the presence of MPR binding antibodies in selected patient sera indicating that this region is immunogenic during the natural in vivo infection process.
176	NEUTRALIZATION-SENSITIVE HIV-1 ELICITS STRONGER NEUTRALIZING ANTIBODY RESPONSES IN INDIVIDUALS WITH RECENT HIV INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 176) Simon Frost¹, S Little¹, T Wrin², Y Liu², C Chappey², C Petropoulos², and D Richman^1,3 Our results support a model in which infection with more neutralization-sensitive virus elicits more powerful neutralizing antibody responses, providing a biological rationale for the use of neutralization sensitive strains as vaccine candidates. More sensitive virus may also have a higher replication rate in vivo.
177	Fcγ RECEPTOR IIa AND IIIa POLYMORPHISMS ARE ASSOCIATED WITH THE RISK OF HIV INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 177) Donald Forthal¹, G Landucci¹, T Phan¹, R Higa-Tanner¹, and P Gilbert² The HHVV genotype may confer protection against sexually transmitted HIV infection in the absence of vaccine-induced antibody. However, after vaccination, individuals with the HHVV genotype are more likely to become infected than those with other genotypes. Thus, rgp120 vaccine appears to enhance the likelihood of infection among HHVV. It is known that HH and VV FcγR bind immune complexes with higher avidity than other genotypes. We found that vaccine-induced antibody titers are higher in infected HHVV vaccinees than in uninfected HHVV vaccinees. These facts support an in vivo role for vaccine-induced antibody-dependent enhancement of HIV infection involving FcγRIIa and IIIa.
178	MONOCLONAL ANTIBODY INFUSIONS DELAY HIV-1 REBOUND AFTER DISCONTINUATION OF ART IN A COHORT OF HIV-1-INFECTED INDIVIDUALS TREATED DURING PRIMARY HIV-1 INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 178) Saurabh Mehandru¹, B Vcelar², M O'Neil¹, T Wrin³, G Stiegler², A Shet¹, J Galovich³, C Petropoulos³, H Katinger², and M Markowitz¹ Monoclonal antibodies delay plasma viral rebound post ART-DC. In general, rebounding virus developed resistance to 2G12; 4E10 and 2F5 did not exert pressure on the virus likely due to rapid clearance and low trough levels of these antibodies in vivo. Testing of other monoclonal antibodies in combination with 2G12 should be evaluated.
179LB	HEXON-CHIMERIC ADENOVIRUS SEROTYPE 5 VECTORS EFFECTIVELY CIRCUMVENT PRE-EXISTING ANTI-VECTOR IMMUNITY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 179LB) D Roberts¹, A Nanda¹, D Lynch¹, B Ewald¹, P Abbink¹, M Havenga², J Goudsmit², and Dan Barouch¹ These data demonstrate that functionally relevant Ad5-specific neutralizing antibodies are highly focused on epitopes within the 7 short hexon HVR in both mice and nonhuman primates. Moreover, these studies show that novel recombinant viral vectors can be engineered to circumvent pre-existing anti-vector immunity by removing key neutralizing epitopes on the surface of viral capsid proteins. HVR-chimeric rAd5 vectors may prove useful as second-generation rAd vector-based vaccines for HIV-1 and other pathogens.
180	IMMUNE RESPONSES THAT SUCCESSFULLY CONTROL AIDS VIRUS REPLICATION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 180) David Watkins The goal of an AIDS vaccine regimen designed to induce cellular immune responses should be to reduce viral set point and preserve memory CD4+ lymphocytes. I will present the rather surprising results of these depletion experiments and discuss their implications for HIV vaccine development. Furthermore, I will present the encouraging results from these studies that suggest that a vaccine designed to induce cellular immune responses might control HIV replication.
Session 50—Poster Abstracts Cellular Defenses and Restriction Factors
200	PEPTIDE INHIBITORS OF IN VITRO BINDING OF HIV-1 Vif TO HUMAN APOBEC3G Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 200) John Donahue, R D'Aquila, D Haas, and C Aiken We have identified Vif and APOBEC3G peptides that specifically inhibit the interaction between human APOBEC3G and HIV-1 Vif in vitro. The identified peptides provide information about the amino acid sequences that may be involved in the interaction of these 2 proteins. This information will facilitate structure/function studies that may lead to the development of rationally designed antiviral agents that target this important intracellular protein–protein interaction in HIV-1-infected cells.
201	PATTERNS IN RETROVIRUS-PRIMATE HOST CO-EVOLUTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 201) Millán Ortiz¹, G Bleiber¹, R Martinez¹, V Goldschmidt¹, H Kaessmann², and A Telenti¹ Comparative phylogenetic analysis underscores the extent of co-evolution of the primate hosts and their SIV species. In contrast to TRIM5 and APOBEC3G, evolutionary analysis at the protein level suggests that PPIA (incorporated into HIV-1) is not under differential pressure in primates. The strong conservation of the TRIM19/PML protein sequences among primates suggests that this gene does not play a role in antiretroviral defense.
202	ENDOGENOUS APOBEC3G PROTEIN EXPRESSION IN NORMAL CD4 T CELLS IS STRONGLY UP-REGULATED AFTER THEIR ACTIVATION AND MOSTLY TRANSLOCATES TO THE NUCLEUS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 202) Harold Oliva¹, M Rodríguez-García¹, N Climent¹, F García¹, M Plana¹, J Miró¹, J Gatell¹, N Navaratnam², and T Gallart¹ In activated CD4+ T cells, the main cell target where HIV replicates, endogenous A3G protein undergoes a strong up-regulation and largely translocates from the cytoplasm to the nucleus. Whether the translocated A3G has anti-HIV activity remains to be determined. Experiments are being done to assess whether A3G is a nucleocytoplasmic shuttling protein, as has been demonstrated for APOBEC1 and activation-induced deaminase (AID).
203	APOBEC3G EXPRESSION IS RESTRICTED TO NEURONS IN THE BRAINS OF PIG-TAILED MACAQUES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 203) M Sarah Hill, L Gomez, J M Miller, and E Stephens These results indicate that APOBEC3G expression is restricted to neurons in the brain and that astrocytes and microglia either do not express this protein or express it at levels undetectable by immunohistochemistry. These finding have implications for the brain as a potential reservoir for Vif-defective viruses.
204	TRIM5α RESTRICTION OF FIV AND HIV-1: LENTIVIRUS AND CELL LINE DEPENDENCE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 204) Dyana Saenz and E Poeschla Rhesus and human TRIM5α proteins restrict FIV in a saturable manner. Stable knock-down of rhesus TRIM5α released HIV-1 and FIV from LV1 restriction. FIV VLP saturated LV1 restriction less effectively than HIV virus-like particles (VLP). Degree of restriction by introduced TRIM5α proteins was dependent on the cell line. A canine cell line supported restriction much less effectively than other cells, raising the possibility that these proteins may not function autonomously or that a canine factor may interfere.
205	VARIATION IN THE ANTIRETROVIRAL PROTEIN TRIM5α IN HUMANS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 205) Valérie Goldschmidt¹, M Ortiz¹, M May², R Martinez¹, H Kaessmann³, G Bleiber¹, and A Telenti¹ Human TRIM5 shows a high sequence variability, with an unusually high number of non-synonymous amino acid substitutions. They occur mainly at evolutionary conserved sites and therefore deserve further analysis; in vivo data would suggest a protective effect for 2 variant alleles-trends that need confirmation in a bigger dataset.
206	EVOLUTION OF CYCLOPHILIN A AND TRIMCyp RETROTRANSPOSITION IN NEW WORLD PRIMATES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 206) I Ribeiro¹, A Menezes², M Moreira², C Bonvicino², H Seuánez^1,2, and Marcelo A. Soares¹ TRIM5-Cyp is characteristic of Aotus genus, and the retrotransposition has happened before the genus radiation. Molecular evolution has diverged the CypA original and retrotransposed copies, likely through neutral selective pressure. Our data underscore the need for a precise taxonomic identification of primate species used as models for retroviral infections and novel antiviral approaches.
207	THE EFFECT OF PROTEASOME INHIBITORS ON TRIM5α EXPRESSION, TURNOVER AND CELL BIOLOGY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 207) Xiaolu Wu¹, J Anderson², E Campbell², A Joseph², and T Hope² TRIM5α turns over rapidly in the cell with a half-life of about 1 hour. MG132 treatment leads to bigger but fewer cytoplasmic bodies without obvious effect on expression level or turnover rate. Thus, proteasome activity does not regulate TRIM5α expression or turnover, but appears to be involved in regulating the cell biology of TRIM5α.
208	INHIBITION OF HIV-1 INFECTIVITY BY THE HUMAN CELLULAR PROLYL ISOMERASE PIN1 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 208) T Uchida¹ and Andrew Saphire² Pin1 is the first example of a host molecular chaperone whose activity restricts HIV-1 infectivity, suggesting that the fate of HIV-1 infection may be balanced on the morphological influence of particular chaperones.
209	DBR1 siRNA INHIBITION OF HIV-1 REPLICATION INDICATES AN RNA LARIAT INTERMEDIATE DURING MINUS-STRAND TRANSFER Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 209) Ying Ye, J De Leon, V Sung, and D Camerini These data indicate that the HIV-1 utilizes an RNA lariat intermediate during minus-strand transfer. This will have profound implications for our understanding of HIV-1 cDNA synthesis.
210	HIV INFECTION IS SUPPRESSED BY G9, A NOVEL INNATE EFFECTOR PROTEIN Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 210) Annapurna Vyakarnam, R Alvarez, and D King G9 blocks 2 stages of the HIV lifecycle: it inhibits HIV production prior to release of virus particles, and it inhibits an entry-dependent step at or prior to reverse transcription. G9 is a small molecular weight, secreted protein; some members of the extended G9 family of proteins have known innate immune activity. Further studies will reveal the mechanisms of the G9 anti-HIV effect and its immunotherapeutic potential.
211	DELETION MAPPING OF THE GB VIRUS C NONSTRUCTURAL PROTEIN 5A IDENTIFIES A 69 AMINO ACID REGION REQUIRED FOR INHIBITION OF HIV REPLICATION IN JURKAT CELLS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 211) Jinhua Xiang, J McLinden, Q Chang, T Kaufman, and J Stapleton Expression of GBV-C NS5A protein inhibits HIV replication independently of its effect on PKR-mediated eIF-2α phosphorylation. A region between amino acids 181 and 250 is required for HIV inhibition. N-terminal deletion mutants have been generated, and cell lines are being selected to further determine the protein requirements for this effect, as are cell lines expressing the NS5A proteins from related viruses (HCV, GBV-B, BVDV, and dengue). Studies on the effects of NS5A mutant proteins on gene expression, chemokine, and chemokine receptor expression are underway. The GBV-C NS5A protein may provide novel, cellular-based approaches to inhibiting HIV replication.
Session 51—Poster Abstracts Vif and APOBEC3G: Mechanisms of Action
212	NUCLEOCAPSID AND RNA MEDIATE PACKAGING OF APOBEC3 PROTEINS INTO RETROVIRAL PARTICLES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 212) Alexandra Schaefer and B Cullen Together, these data suggest that RNA packaging by retroviruses and LTR-retrotransposons may involve a highly conserved intermediate that is recognized as a pathogen-associated molecular pattern (PAMP) by host APOBEC3 proteins.
213	THE HIV-1 VIF PROTEIN INHIBITS APOBEC3G PACKAGING INTO VIRIONS THROUGH A COMPETITIVE MECHANISM Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 213) Mohammad Khan, S Kao, R Goila-gaur, E Miyagi, H Takeuchi, S Opi, and K Strebel Thus, Vif-induced degradation of APO3G and competitive inhibition of APO3G encapsidation by Vif both contribute to the exclusion of APO3G from HIV virions, thereby ensuring the production of fully infectious virus particles.
214	COOPERATIVE AND SPECIFIC BINDING OF VIF TO THE 5' REGION OF HIV-1 RNA Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 214) Simon Henriet¹, D Richer¹, S Bernacchi¹, E Decroly², R Vigne², J C Paillart¹, and R Marquet¹ Combination of biochemical and biophysical approaches allowed us to characterize the RNA-binding properties of Vif. Our study showed cooperative and preferential binding of Vif to the 5' region of the HIV-1 genomic RNA, in which minimal high binding sites were also identified. Taken together, our results suggest that Vif may assist other viral or cellular proteins to maintain a correct folding of the HIV-1 genomic RNA in order to facilitate its packaging and further steps such as reverse transcription. Vif-RNA interaction could also play a role in viral RNA/DNA protection from deamination by APOBEC proteins.
215	MURINE LEUKEMIA VIRUS ESCAPES FROM MURINE APOBEC3 VIA 2 DISTINCT MECHANISMS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 215) Aierken Abudu, A Takaori-Kondo, K Shirakawa, T Izumi, A Sasada, M Tomonaga, and T Uchiyama MLV escapes from mA3 by 2 different mechanisms, exclusion by viral RNA and cleavage by viral PR.
216	THE INHIBITION OF tRNA^Lys3-PRIMED REVERSE TRANSCRIPTION IN HIV-1 BY HUMAN APOBEC3F AND MOUSE APOBEC3G Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 216) Yiliang Yang, F Gou, S Cen, M Niu, and L Kleiman Our results demonstrate that a novel inhibition of the mechanism that contributes to the antiviral function of hA3F and mA3G is the inhibition of tRNA^Lys3-primed reverse transcription in HIV-1.
217	MUTATIONAL ALTERATION OF HIV-1 VIF ALLOWS FUNCTIONAL INTERACTION WITH PRIMATE APOBEC3 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 217) Barbel Schrofelbauer¹, T Senger^1,2, and N Landau¹ The effect of replacement of specific positive charges on HIV-1 Vif suggests a complementary interaction of the amino-terminal domain of Vif with amino acid 128 on APOBEC3G. A necessary step toward the establishment of a primate animal model for HIV-1 is to overcome the APOBEC3 block. These findings provide an important advance toward achieving this goal.
218	THE INTERACTION BETWEEN HIV-1 GAG AND APOBEC3F Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 218) Li Zhang, Y Yang, F Gou, J Saadatmand, M Niu, L Kleiman, and S Cen Our data indicate that hA3F is incorporated into HIV-1 through the similar mechanism to that of hA3G. Compared with hA3G, hA3F is packaged into HIV-1 less efficiently, suggesting that HIV-1 might not be the primary target for hA3F.
219	THE EFFECTS OF CYTOSINE DEAMINASE ACTIVITY ON LENTIVIRAL PERSISTENCE IN VITRO AND IN VIVO: DEVELOPMENT OF FIV AS A RELEVANT MODEL SYSTEM Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 219) Jennifer Troyer¹, J Terwee¹, M Poss², and S Vandewoude¹ Intracellular restriction mechanisms facilitate cross-species lentiviral containment. We have developed an in vivo system to examine the importance of this mechanism of viral control relative to adaptive immune effects. Future studies will determine how such mechanisms can be engineered to restrict or eliminate infection by virulent host-adapted lentiviral strains.
Session 52—Poster Abstracts Viral Envelope: Tropism and Trans Infection
220	STRUCTURAL ANALYSIS INDICATES THAT HIV ENVELOPE BINDING TO DC-SIGN INVOLVES 2G12 BINDING SITE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 220) Won-Pyo Hong, S Nguyen, S Su, and B Lee DC-SIGN can bind to broader range of N-linked glycosylation sites than 2G12 on HIV gp120; however, its preferential binding site overlaps with the 2G12 epitope.
221	THE V2 LOOP IS A MAJOR DETERMINANT OF SIV_sm ENVELOPE ADAPTATION TO RHESUS MACAQUES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 221) Thomas Vanderford¹, L Demma², M Feinberg³, S Staprans¹, and J Logsdon⁴ Strong species-specific positive selection in the V2 loop at days 40 and 70 underscores its importance in adaptation of SIV_sm to rhesus macaques. Since neutralizing antibody responses are low or not yet present, these changes may be adaptations to a divergent CD4 receptor or co-receptor. Examining how SIV_sm adapts to non-natural hosts may help us to understand and prevent cross-species transmission of other deadly RNA viruses.
222	REPLICATION-COMPETENT VARIANTS OF HIV-1 CONTAINING DELETIONS WITHIN THE V3 LOOP Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 222) Mark Biscone, K McGeehan, A Polachini De Oliveira, B Haggarty, J Romano, R Doms, and J Hoxie HIV-1 can be derived with partial deletions of the V3 loop. The location of these deletions can have profound effects on X4 vs R5 tropism. These findings suggest that subdomains within V3 can be identified that contribute to the differential use of X4 and R5. Our findings also show that a deletion of the V3 crown results in resistance to small-molecule inhibitors of CCR5. These studies reveal a novel approach for analyzing Env structure and function and possibly for developing new classes of antiviral drugs that target CCR5.
223	LOSS OF N-LINKED GLYCOSYLATION IN HIV-1 SUBTYPE C ENVELOPE GLYCOPROTEIN IS A MAJOR DETERMINANT OF CCR5-TO-CXCR4 SWITCH IN CO-RECEPTOR USAGE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 23) Thomas Ndolo¹, E Johnston², A Aggrawal³, M Vajaypayee³, P Seth³, D Katzenstein², and S Dandekar¹ In primary, subtype C isolates from India and Zimbabwe, higher and lower ratio of positive charges in V3 : V3/V4V5 glycosylation sites is associated with CXCR4 and CCR5 tropism, respectively. Loss of N-linked glycosylation sites within the V3/V4/V5 regions in addition to the presence of a positively charged amino acid and an intermediate net positive charge within the V3 loop predicted CXCR4 co-receptor usage in primary HIV-1 subtype C viruses. This may be explained by receptor ligand binding and or immune evasion. N-glycosylation may provide an additional subtype C-specific predictor for characterizing co-receptor usage.
224	A 5 AMINO ACID INSERT WITHIN THE V3 LOOP OF HIV-1 ENVELOPE APPEARS TO BE DERIVED FROM THE HUMAN GENOME Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 224) Elizabeth Johnston, B McColgan, and D Katzenstein Immune escape, drug resistance, and co-receptor switching are usually the result of multiple point mutations. In this unusual virus, the V3 loop accommodated a 15-base-pair insert, homologous to human transcription factor DNA. Recombination, incorporating DNA from the host, provides an additional mechanism for increasing HIV diversity.
225	DIFFERENTIAL BEHAVIOR OF GLYCOPROTEINS GP120 FROM ACUTE HIV-1 INFECTIONS IN THE DC-SIGN PATHWAY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 225) Alexandra Vallon-Eberhard, MM Fiers-Didelot, F Giroux, F Reynard, C Guillon, F Bedin, and B Verrier There are inter- and intra-sequence variations in the behavior of gp120 from acute infection in the interactions with DC-SIGN, suggesting that selection of a specific viral strain among a quasi-species may occur at different steps. This study has allowed us to select 2 clones of interest: 1 with a high affinity to DC-SIGN without internalization, and 1 efficiently transmitted and with a high resistance to potential microbicides.
226	DONOR AND RECIPIENT ENV FROM HETEROSEXUAL TRANSMISSION PAIRS REQUIRE HIGH RECEPTOR LEVELS FOR ENTRY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 226) Melissa Alexander¹, E Platt², J Mulenga³, S Allen¹, D Kabat², C Derdeyn¹, and E Hunter¹ There appears to be no difference in the efficiency of receptor utilization between the donor and recipient Env in these HeLa-derived cell lines. The requirement for high levels of CD4 and CCR5 by both newly transmitted Env and those from chronic infection suggests that the observed genetic bottleneck does not involve the ability to utilize low levels of CD4 or CCR5 or both.
227	RELATIVE UTILIZATION AND T20 SENSITIVITY OF CCR5- AND CXCR4-MEDIATED ENTRY BY R5X4 ISOLATES INTO PRIMARY MACROPHAGES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 227) Yanjie Yi, L Loftin, and R Collman R5X4 isolates are functionally X4 on lymphocytes but R5X4 on macrophages, suggesting that viral evolution involves an expansion of co-receptor use in macrophages, but a switch from R5 to X4 in lymphocytes. However, R5X4 strains differ quantitatively in relative utilization of each entry pathway in macrophages. Surprisingly, blocking 1 entry pathway on macrophages does not result in a compensatory increase in entry through the other pathway, even though it is likely that virus, and not co-receptor, availability is limiting. Finally, based on T20 sensitivity assay, R5X4 isolates use macrophage CCR5 and CXCR4 with comparable efficiency, and with similar efficiency to that of the R5 and X4 reference strains BAL and Tybe.
228	GLOBAL GENE EXPRESSION PROFILES ALTERED IN PRIMARY MACROPHAGES BY HIV-1 M-R5 BUT NOT T-X4 ENVELOPE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 228) Joseph Brown¹, J Kohler¹, J Sleasman², and M Goodenow¹ In contrast to T-X4 envelope, M-R5 envelopes induce distinct gene expression profiles in macrophages. D-X4 envelope signals in macrophages, but with delayed kinetics compared to M-R5. Results suggest that envelope signaling serves as a “priming factor” to permit viral entry and replication. Differences in transcriptomes of primary macrophages as a consequence of envelope signaling through CCR5 as opposed to CXCR4 represent novel therapeutic targets to control viral replication.
229	PRIMARY HIV-1-ONLY-USING ISOLATES DO NOT ACCURATELY REPRESENT THE IN VIVO REPLICATING QUASI-SPECIES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 229) M Aasa-Chapman, K Aubin, C Seymore, I Williams, and Aine McKnight Virus isolation by PBMC co-culture favors the selection of CCR5-only-using viruses. Our results suggest a selective pressure in vivo to maintain CCR3 use.
230	KINETIC ANALYSIS OF ENVELOPE-MEDIATED FUSION OF CXCR4- AND CCR5-TROPIC HIV-1 USING A TEMPERATURE-ARRESTED INTERMEDIATE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 230) Hamani Henderson¹ and T Hope² This kinetic analysis can be used as a tool to synchronize entry and study HIV fusion. Our data suggest that a temperature-arrested intermediate contributes to the exposure of heptad repeats within gp41 that are necessary for 6-helix bundle formation. Further, the time required to become resistant to TAK779 is less after the temperature-arrested stage than before. These data imply that a temperature-arrested stage provides a kinetic predisposition for engagement of CCR5 by virion-associated gp120.
231	SUBSTITUTION OF MEMBRANE ACTIVE PEPTIDES INTO THE HIV-1 TRYPTOPHAN-RICH MEMBRANE PROXIMAL EXTERNAL REGION OF gp41 CAN PRESERVE FUSION BUT NOT INFECTIVITY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 231) Sundaram Ajay Vishwanathan and E Hunter The replacement of HIV-1 gp41 MPER with a proline-rich membrane-disruptive peptide does not prevent fusion, strongly indicating that the aromatic collar and α-helical potential are not essential for this function. In contrast, the same substitutions effectively block viral entry, suggesting that other structural constraints are imposed on this region, possibly at the level of glycoprotein incorporation.
232	HIV-1 GAG REGULATES ENVELOPE ASSOCIATION WITH DETERGENT RESISTANT MEMBRANES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 232) J Bhattacharya, A Repik, and Paul Clapham Our observations indicate that gag-envelope interactions are essential for efficient envelope association with lipid rafts, which in turn is required for optimal assembly of envelope onto virus particles.
233	HIV-1 CO-RECEPTOR TROPISM IN TRIPLE-CLASS-EXPERIENCED PATIENTS: BASELINE CORRELATES AND RELATIONSHIP TO ENFUVIRTIDE RESPONSE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 233) Thomas Melby¹, M Despirito¹, R Demasi¹, M Greenberg¹, G Heilek-Snyder², and N Graham¹ D/M tropism was observed in nearly half of this triple-class-experienced population, including 40% of patients with baseline CD4 >200. Virologic and immunologic responses to treatment with ENF did not differ according to baseline virus tropism. At the population level, a shift from D/M to R5 tropism in ENF + OB patients was observed; further studies will be needed to determine whether this effect was lasting or transient and whether it related specifically to ENF or to other factors including a generalized treatment response.
234	MATURE MONOCYTE-DERIVED DENDRITIC CELLS CAPTURE AND TRANS-INFECT HIV-1 INDEPENDENTLY OF DC-SIGN Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 234) Nuria Izquierdo Useros, J Blanco, M Fernández-Figueras, I Erkizia, P Parrales, L Ruiz, B Clotet, and J Martinez Picado mMDDC display an enhanced capture and trans-infection ability compared with iMDDC, although this cell type displays fewer DC-SIGN antibody molecules bound per cell. DC-SIGN inhibitors do not efficiently block mMDDC Trans-infection, suggesting that other mechanisms involved in HIV capture besides mannose binding C-type lectin receptors.
235	EFFECT OF POLYMORPHISMS IN THE DC-SIGNR NECK DOMAIN ON THE INTERACTION WITH HIV-1 AND OTHER PATHOGENS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 235) Thomas Gramberg^1,2, H Hofmann³, C Chaipan^1,2, A Marzi^1,2, H Liu⁴, T Andrus⁴, T Zhu⁴, S Pöhlmann^1,2, and A Wegele^1,2 Thus, our results do not provide evidence for diminished pathogen capture by DC-SIGNR alleles with 5 and 6 repeat units. Albeit we cannot exclude that subtle, but in vivo relevant differences remained undetected, our analysis suggests that indirect mechanisms might account for the association of polymorphisms in the DC-SIGNR neck region with reduced risk of HIV-1 infection.
236	ROLE OF L-SELECTIN CD62L IN VIRUS ATTACHMENT ON ENDOTHELIAL CELLS AND TRANS-INFECTION OF CD4+ T LYMPHOCYTES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 236) Sandra Thibault and M Tremblay Taken together, these results suggest that CD62L play an important role in attachment of HIV-1 particles to endothelial cells, a phenomenon linked to a better HIV-1 transfer toward CD4+ T lymphocytes. Additional work is needed to shed light on the CD62 ligand(s) responsible for the observed phenomenon and also to define whether other step(s) in virus life cycle can be affected upon acquisition of CD62L. These observations confirm that host-derived proteins located on the exterior of HIV-1 can modulate the biology of this retrovirus.
Session 53—Poster Abstracts Cellular Co-Factors for Virus Replication
237	POTENT INHIBITION OF HIV-1 REPLICATION BY OVER-EXPRESSION OF THE INTEGRASE BINDING DOMAIN OF LEDGF/p75 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 237) Linos Vandekerckhove, J De Rijck, F Christ, B Poddesu, J Vercammen, B Van Maele, Y Engelborghs, R Gijsbers, and Z Debyser The highly potent inhibition of HIV-1 replication obtained in cell lines over-expressing the IBD of LEDGF, corroborates the importance of IN-LEDGF/p75 interaction for viral replication. Over-expression of IBD provides a proof-of-principle for a novel antiviral strategy targeting the interaction of LEDGF/p75 with HIV-1 IN. Although the EGFP-IBD and EGFP-Δ325 proteins relocalized to the cytoplasm in the presence of mRFP-IN, the replication block was not found at the stage of nuclear import but during viral integration. By binding to HIV-1 integrase, the IBD likely competes with the binding of native LEDGF/p75 that is required to dock the preintegration complex to the chromosomes.
238	ACETYLATION OF HIV-1 INTEGRASE BY THE CELLULAR HISTONE ACETYLTRANSFERASE GCN5 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 238) Mariaelena Terreni¹, A Fittipaldi¹, M Giacca^1,2, and A Cereseto¹ The results show that, in addition to p300, GCN5 acetylates IN, indicating the relevance of this newly identified modification in the biology of this viral protein.
239	HISTONE DEACETYLASE 6 REGULATES HIV-1 INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 239) Marta Barrero¹, A Valenzuela-Fernández¹, M Muñoz-Fernandez², and F Sanchez-Madrid¹ Our results indicate that HDAC6 plays a significant role in regulating HIV-1 infection and Env-mediated syncytia formation.
240	TIP47, A PROTEIN ESSENTIAL FOR THE HIV-1 ENVELOPE GLYCOPROTEIN INCORPORATION INTO VIRIONS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 240) S Lopez-Vergès, G Camus, G Blot, R Beauvoir, R Benarous, and Clarisse Berlioz-Torrent Altogether, our data demonstrate that TIP47 is an essential cellular co-factor required for Env incorporation into HIV-1 virions.
241	HIV-1 REV AND NC FUNCTIONS ARE AFFECTED BY PRMT6 ARGININE METHYLATIONS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 241) Cédric Invernizzi, F Frankel, B Xie, B Spira, and M Wainberg Both Rev and NC are modified by PRMT6. These arginine methylations negatively affect RRE binding of Rev and primer annealing by NC. These findings, together with work showing that Tat function is negatively affected by arginine methylation, suggest that methylation of viral proteins by PRMT6 may be an anti-HIV host defense mechanism.
242	A NOVEL POST-TRANSCRIPTIONAL BLOCK IN HIV GENE EXPRESSION CONTRIBUTES TO LATENCY IN VIVO Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 242) Kara Lassen¹, K Ramyar², J Bailey², Y Zhou², R Siliciano², and J Karn¹ Latently infected resting CD4+ T cells exhibit multiple blocks in gene expression. Here we describe a novel post-transcriptional block at the level of HIV-1 RNA export that interrupts the Tat-dependent feedback loop restricting transcription. We are currently examining the role of PTB in HIV-1 gene expression in a cellular model system. PTB permits positive feedback amplification of viral gene expression and reverses latency without inducing cellular stimulation, a result with therapeutic implications.
243	VPS28 ACTS TO STABILIZE TSG101 BY PREVENTING ITS DEGRADATION BY TSG101-ASSOCIATED LIGASE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 243) Bethan McDonald and J Martin-Serrano These results suggest that Tal binds Tsg101 at the UEV domain and acts to ubiquitinate the lysine residues at the C-terminal, VPS28 binding region. VPS28 binds very closely to the Tal ubiquitination sites and therefore blocks Tal-mediated Tsg101 degradation. Thus, complexed Tsg101 is protected from Tal by VPS28, suggesting that this is the mechanism to remove free, un-complexed Tsg101.
244	ESCRT-II AND ESCRT-III COMPLEXES IN HIV BUDDING Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 244) Uta Von Schwedler, C Langelier, D Ward, and W Sundquist Thus, it seems that the human ESCRT-II complex is not required for viral budding. CHMP6, even though assumed to be the crucial link of the ESCRT-III complex to membranes, is also dispensable, or replaceable by other CHMP proteins of the same family. The trafficking pathway in human cells is probably less linear and more diverse than in yeast.
245	TETRASPANINS CD9 AND CD81 MODULATE HIV-1-INDUCED MEMBRANE FUSION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 245) Mónica Gordón-Alonso¹, M Yañez-Mó¹, O Barreiro¹, S Álvarez², M Muñoz-Fernández², A Valenzuela-Fernández¹, and F Sánchez-Madrid¹ These data indicate that CD9 and CD81 have an important role in membrane fusion induced by HIV-1. Moreover, our observations highlight the importance of target cell state in viral transmission concerning protein organization on the plasma membrane.
Session 54—Poster Abstracts Viral Transcription and Transactivation
246	RAPID SHUTDOWN OF HIV TRANSCRIPTION IN CELLS INFECTED WITH VIRUSES EXPRESSING TAT WITH A HIGH THRESHOLD FOR LTR ACTIVATION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 246) Richard Pearson, Y Kim, D McDonald, and J Karn The progressive shutdown of HIV transcription exhibited by the H13L viruses suggests that cellular mechanisms restricting HIV transcription initiation can lead to the eventual decline of Tat to levels that no longer sustain efficient HIV expression. We are currently using ChIP assays to explore possible mechanisms of shutdown in this population, including the development of restrictive chromatin structures on the integrated proviruses.
247	HIGHER TRANSACTIVATION ACTIVITY ASSOCIATED WITH LTR AND TAT ELEMENTS FROM BF INTERSUBTYPE RECOMBINANT VARIANTS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 247) Gabriela Turk, M Carobene, A Monczor, A Rubio, M Gomez-Carrillo, and H Salomon Data presented here show transcriptional differences associated with the LTR and Tat coding region from BF recombinants circulating in Argentina. Although LTR and Tat sequences were thoroughly studied and several changes were observed, no direct relationship between these changes and transcriptional level differences could be established. This improvement might be a consequence of the recombination process between 2 different HIV-1 subtypes. Selection forces would have favored the spreading of these recombinant forms. To our knowledge, this is the first work that shows higher transcriptional activity of a widely spread HIV-1 circulating recombinant form than its pure subtype counterpart.
248	ATTENUATION OF MULTIPLY SPLICED RNA LEVELS IN PBMC OF PATIENTS ON ART IS DUE TO HETEROGENEOUS REDUCTION OF DISTINCT CLASSES OF INFECTED CD4+T CELLS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 248) Philipp Kaiser¹, B Joos¹, B Niederöst¹, E Niederer², R Weber¹, H Günthard¹, and M Fischer¹ Combination of limiting dilution with isolate-matched quantitative rtPCR allowed us to quantify frequencies of infected peripheral CD4+ T cells and monocytes and to specify patterns of low, intermediate, and high viral transcriptional activity. Peripheral monocytes appeared to play a minor role as site of HIV-transcription in either patient group. In CD4+ T cells, irrespective of their activation status, ART was associated with quasi extinction of elevated transcriptional patterns, whereas decrease was much less pronounced in classes with basal activity. In a substantial part of infected cells MsRNA persisted, and complete shut down was not observed.
249	ALTERATIONS IN ENHANCER/PROMOTER SPACING EFFECT HIV REPLICATION IN A CELL-SPECIFIC MANNER Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 249) Kendra Mack, D Petrik, G Schulert, J Storlie, and W Maury These results suggest that transcriptional regulation of HIV in macrophages fundamentally differs from that in T cells. A strict positionally dependent interaction between the HIV enhancer region and the promoter was required for HIV transcription and replication in T cells. Greater flexibility was observed in macrophages. Infectivity studies with the altered spacing panel are ongoing. Our findings indicate that by altering the enhancer/promoter spacing macrophage specific HIV viruses can be generated.
250	REGULATION OF SDF-1/CXCL12 EXPRESSION BY THE TAX PROTEIN OF HTLV-I Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 250) Mercedes Bermejo¹, J Alonso-Lobo¹, L Sanchez², S Mori³, A Caruz⁴, F Arenzana-Seisdedos⁵, and J Alcami¹ Tax protein from HTLV-1 induces the expression of the chemokine SDF-1/CXCL12 at transcriptional level. Accordingly, abnormal CXCL12 production was found in HTLV-1-infected cell lines and biopsies from HTLV-1-associated lymphomas. This increase in CXCL12 expression by Tax may contribute to homing of lymphocytes towards HTLV-1-infected lymph nodes, thus enhancing HTLV-1 propagation.
251	ROLE OF HTLV-1 TAX IN SHP-1 PROMOTER SILENCING DURING HTLV-1 LEUKEMOGENESIS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 251) Jihua Cheng, A Kydd, H Tao, Q Zhu, and W Marasco These data indicate that Shp-1 P2 promoter activity is NF-κB dependent and HDAC1-NF-κB plays key roles in Shp-1 promoter silencing during HTLV-1 leukemogenesis. As DNA methylation is also known to play a role in this procedure, as published by other research groups, our results highlight the complex nature of Tax-induced promoter silencing, which requires further investigation.
Session 55—Poster Abstracts Viral Accessory Genes
252	NEF REGULATES p21-GTPase ACTIVITY AND ASSOCIATES WITH PAK2 IN A p21-GTPase-DEPENDENT MANNER Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 252) Kati Pulkkinen¹ and K Saksela² Functional GTPase-binding domain is essential for Nef/PAK2 association, but not only for enabling p21-mediated activation of PAK2. Ability of Nef to activate Rac in an allele-independent manner suggests GTPase activation as a conserved function of Nef. Decreased Rac activation by Vav inhibition supports the role of Vav as one, but not as the sole, mediator of Rac activation by Nef.
253	A HYDROPHOBIC BINDING SURFACE ON THE HIV-1 NEF CORE IS CRITICAL FOR ASSOCIATION WITH p21-ACTIVATED KINASE 2 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 253) K Agopian¹, B Wei², J Garcia², and Dana Gabuzda^1,3 Nef amino acids at positions 85, 89, 187, 188, and 191 are specifically required for Pak2 association. We propose that these Nef residues form part of a unique binding surface critical for association with Pak2. This hydrophobic binding surface may interact directly with Pak2 or may participate in an as-yet-unidentified protein–protein interaction that facilitates Pak2 association and activation.
254	INCREASED EXOCYTOSIS IN NEF-EXPRESSING T CELLS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 254) Claudia Muratori¹, A Tinari¹, F Superti¹, M Federico¹, and A Baur² We conclude that Nef-induced endocytosis directly correlates with increased exocytosis, resulting in the non-physiological stimulation of the secretory system in T cells by which HIV could exert bystander effects on non-infected cells.
255	HIV-1 NEF ENHANCES VIRAL TRANSCRIPTION IN T CELLS THROUGH DEREPRESSION AND NOT ACTIVATION OF NFκB Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 255) Vanessa Witte and A Baur Our results are consistent with the concept that p100 binds to the HIV promoter together with HDAC and possibly Eed to repress transcription. Nef expression leads to the dissociation of this complex through the recruitment of its components to the cytoplasm. Although this induces certain signaling events, such as kinase activation, NFκB is not activated. Thus the function of the Nef-associated complex remains unknown. However, it is conceivable that the removal of repressive factors from the LTR might allow the binding of transcription factors constitutively present in the nucleus and thus suffices to start HIV transcription.
256	HIV-1 VPU AFFECTS THE TRAFFICKING OF ENV AND VIRAL INFECTIVITY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 256) John C Guatelli^1,2 and N Van Damme² Vpu directs Env away from Gag during viral assembly, shifting Env from a clathrin-coated to a non-clathrin-coated endosomal compartment. Consistent with this direction of Env away from Gag, Vpu causes the production of particles of reduced infectivity, even while enhancing numerically their release. Consequently, the net infectivity of the media surrounding cells infected by HIV-1 is unaffected by Vpu. Instead, Vpu affects the distribution of infectivity, yielding the production of more virions that are relatively less infectious.
257	A SINGLE AMINO ACID SUBSTITUTION IN THE VPU VIROPORIN CONVERTS SIMIAN/HUMAN IMMUNODEFICIENCY VIRUS INTO A RIMANTADINE-SENSITIVE VIRUS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 257) M Hill, D Hout, L Gomez, J M Miller, and Edward Stephens These data indicate that the Vpu protein of HIV-1 can be converted into a rimantadine-sensitive ion channel with the alteration of a single amino acid and provide additional evidence the Vpu transmembrane domain forms an ion channel and that drugs targeting the Vpu transmembrane domain/ion channel can be effective anti-HIV-1 drugs.
258	SILENCING OF BOTH β-TrCP1 AND HOS (β-TrCP2) IS REQUIRED TO SUPPRESS HIV-1 VPU-MEDIATED CD4 DOWN-MODULATION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 258) Christophe Butticaz, J Wyniger, M Muñoz, O Michielin, A Telenti, and S Rothenberger β-TrCP2 shares with β-TrCP1 the capacity to bind Vpu. Silencing of both genes is required to suppress HIV-1 Vpu-mediated CD4 down-modulation, and to maximally limit the role of β-TrCP in the HIV-1 cycle.
259	HSP27 AS A POTENTIAL INNATE ANTIVIRAL FACTOR COUNTERACTED BY HIV-1 VIRAL PROTEIN R Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 259) Dong Liang¹, E Agbottah², W Kabat³, M Bukrinsky², and R Zhao¹ This finding could potentially provide a new approach to reducing Vpr-mediated detrimental effects in HIV-infected patients by stimulating small heat shock proteins.
260	THE ROLE OF CYCLOPHILIN A IN HIV-1 VPR-INDUCED CELL CYCLE ARREST Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 260) Orly Ardon and V Planelles We propose that the interaction with CypA is irrelevant to Vpr’s ability to induce cell cycle arrest. The interaction between Vpr and CypA remains intriguing, and further experiments should examine its potential effect on other reported cellular functions of Vpr.
Session 56—Poster Abstracts RNA Packaging, Reverse Transcription and Integration
261	THE RELATIONSHIP BETWEEN RETROVIRAL INTEGRATION AND HOST CELL TRANSCRIPTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 261) Lori Maxfield, N Bell, C Fraize, and J Coffin Possible models for our observation are as follows. First, when a DNA template is undergoing active transcription, integration might be blocked by the RNA pol II complex due to steric hindrance. Alternatively, the integrase complex may require DNA to be in a double-stranded conformation, which would not be the case during active transcription. Finally, transcription might lead to remodeling of chromatin into a structure less favorable for integration.
262	INTEGRATION PATTERNS OF LENTIVIRAL VECTORS IN TRANSGENIC MICE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 262) Alexander Dorr¹, M O Sauvain¹, B Stevenson², M Wiznerowicz¹, and D Trono¹ While our data indicate that the pattern of lentiviral integration in primate and rodent cells are related, the specifics of a cellular environment can markedly influence integration.
263	ANALYSIS OF THE SYMMETRICAL BASE PREFERENCES SURROUNDING HIV-1, ASLV, AND MLV INTEGRATION SITES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 263) Alexander Holman and J Coffin The absence of an absolute consensus suggests that DNA primary sequence shapes structural characteristics optimal for integration. The macro-scale preferences do not correlate to micro-scale preferred sequences, indicating that while regional effects may cause DNA to become accessible to the integration machinery, micro-scale effects seem to regulate actual target site choice. The symmetry within the preferred sequence and the linkage between offsets suggests targeting synergy between the 2 ends of the viral genome.
264	CHARACTERIZATION OF THE 5' TERMINAL DIMERIZATION DOMAIN OF HIV-1 GENOME Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 264) R Song, J Kafaie, M Laughrea, Yiliang Yang, and Y Yang We found that the PBSh plays a more important role in genomic RNA dimerization than the DIS, and regions other than the DIS in the 5’ end of HIV-1 genome also contain dimerization signals. So the 5’ terminal dimerization domain must consist of at least 2 independent dimerization signals.
265	THE CENTRAL DNA FLAP IS CRITICALLY IMPORTANT FOR HIV REPLICATION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 265) Jan De Rijck, L Vandekerckhove, and Z Debyser These results unambiguously demonstrate that the HIV-1 DNA flap is indeed of critical importance for HIV-1 replication especially at low multiplicity of infection.
Session 57—Poster Abstracts RNA Interference Studies
266	PROMOTER TARGETED siRNA SILENCE HIV-1 BY A TRANSCRIPTIONAL GENE SILENCING, WITH MINIMAL CONTRIBUTION FROM A POST-TRANSCRIPTIONAL MECHANISM Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 266) Kazuo Suzuki¹, T Ishida², H Lim¹, T Watanabe², D Cooper³, and A Kelleher³ These results provide further evidence that previously reported siRNA targeting U3 section of 5’LTR act predominantly by a TGS mechanism because they do not reduce the level of 3’LTR RNA transcripts in this model where the 3’LTR is isolated from the 5’LTR.
267	HIV-1 SEQUENCE HOMOLOGY REQUIREMENTS TO ESCAPE FROM SHORT INTERFERING RNA Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 267) Mireia Gimenez-Barcons, R Sabariegos, N Tapia, B Clotet, and M Martinez Our results show that optimal HIV-1 gene silencing by siRNA requires a complete homology within most of the target sequence and that only substitutions at a few positions at the 5´ and 3´ end are partially tolerated.
Session 58—Poster Abstracts Viral Fitness, Evolution, Recombination and Gag Processing
268	SIV VARIANTS THAT DIFFER IN PATHOGENICITY DIFFER IN FITNESS UNDER RAPID CELL-TURNOVER CONDITIONS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 268) Yegor Voronin, J Overbaugh, and M Emerman Late-stage virus SIV_Mne170 was better adapted to rapid turnover of infected cells in vitro. This adaptation may result from in vivo selective pressure imposed by rapid clearance of infected cells by the host immune system and may contribute to increased pathogenicity of SIV_Mne170 in virus-naïve macaques. Because the relative fitness of SIV_MneCL8 and SIV_Mne170 observed in rapid-turnover system more accurately reflects their fitness in vivo, the system represents an approach to comparing relative fitness of viruses that may better mimic viral replication in the host. Current work focuses on testing whether HIV variants isolated from late-stage patients are more fit in rapid-turnover system than early isolates.
269	RECOMBINATION BREAK-POINTS DETECTED IN C-TERMINAL PROTEASE AND N-TERMINAL RT REGIONS OF HIV-1 UNIQUE RECOMBINANT FORMS DO NOT INFLUENCE VIRAL REPLICATION CAPABILITY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 269) Andrea Galli¹, A Lai¹, S Corvasce¹, F Saladini², C Riva¹, L Deho¹, L Romano², M Galli¹, M Zazzi², and C Balotta¹ Since all samples were obtained from patients with an active infection, our data indicate that recombination involving at least the first 150 amino acids of RT seems not to interfere with viral replication capacity. No assumptions can be drawn regarding viral fitness or infectiveness because the URF studied could have been either generated in the individual host or acquired through infection. Break-points randomly involving the first ~61 amino acids of protease apparently produce viruses unable to replicate, not found in the viral species of the host. It is noteworthy that this region encompasses the entire PR flap region and the active site. Finally, the numerous break-points found in the relatively narrow RT finger region could indicate the presence of a recombination hot-spot caused by underlying RNA sequence or structural features.
270	RECOMBINATION DURING INTRACLADE HIV DUAL INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 270) Sergei Kosakovsky Pond¹, D Smith¹, C Chappey², T Wrin², Y Liu², D Richman^1,3, S Little¹, S Frost¹, and E Daar⁴ Robust detection of recombination by 2 viruses of the same clade requires specialized techniques, such as genetic algorithms, because of relative genetic similarity of viral sequences. Recombination allows for a more rapid increase in viral diversity than the accumulation of mutations through replication errors. This genetic heterogeneity can facilitate rapid adaptation to host immune responses, target cell availability and ART, and lead to increased viral pathogenicity and reduced antiretroviral susceptibility, both of which have been documented after superinfection.
271	EVOLUTION OF HIV-1 CTL EPITOPES: BALANCE BETWEEN CTL ESCAPE AND FITNESS CONSTRAINTS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 271) Yi Liu¹, H Zhao¹, J McNevin², I Genowati¹, M McSweyn², D Shriner³, M McElrath², and J Mullins¹ Although CTL responses selected for escape mutants, many potentially have fitness costs. The balance between the advantage of escaping from immune responses and the disadvantage of losing replicative fitness plays an important role in determining whether a CTL epitope will persist or by replaced by escape mutants during infection.
272	ANALYSIS OF CLEAVAGE SITE DETERMINANTS WITHIN HIV-1 SUBTYPE A, B, AND C GAG POLYPROTEINS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 272) Roxana Coman, I Munoz, M Goodenow, and B Dunn The pattern of cleavages of subtype A, B, and C Gag polyprotein, independent of the subtype of the protease added in trans, is noticeably similar, indicating that there are determinants in Gag that modulate the processing events. Additional proof is brought by the 3-fold increase in p24/p25 yield after the introduction of S124V mutation at P5 position of MA/CA cleavage site.
Session 59—Poster Abstracts Tropism: Receptors/Co-Receptors
273	CCR5 AND CXCR4 CO-RECEPTORS ARE HIGHLY EXPRESSED ON LYMPH NODE FOLLICULAR CD4+ T CELLS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 273) Amie Meditz, J Folkvord, M McCarter, and E Connick CCR5 and CXCR4 are highly expressed on lymph node follicular (CD57+) CD4+ T cells in both HIV+ and HIV individuals and likely enhance their susceptibility to HIV infection. Exploitation of the normal physiologic high expression of chemokine receptors on follicular CD4+ T cells by HIV likely contributes to the concentration of virus replication within lymphoid follicles.
274	EVOLUTION OF HIV-1 ENVELOPE FUNCTION DURING CO-RECEPTOR SWITCHING Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 274) C Pastore¹, R Nedellec¹, A Ramos¹, S Pontow², L Ratner², J Miamidian³, J Reeves³, and Donald Mosier¹ The transition from R5 to X4 co-receptor use is associated with a loss of CCR5 binding but a stabilization or increase in CD4 binding. A dramatic loss in CCR5-mediated binding and entry caused by V3 mutations appears to be stabilized by compensatory mutations in V2 that increase CD4 binding and allow inefficient use of CXCR4 to be improved.
275	DIFFERENTIAL SIGNALING EFFECTS OF R5 AND X4 GP120 ON PRIMARY CD4+ T CELLS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 275) Vicky Sung and D Camerini Our data suggest that the diverse effects of R5 and X4 HIV-1 gp120 interaction with CCR5 and CXCR4 may affect the infection of resting cells and impart a selection for R5 HIV-1 following transmission and during the asymptomatic phase of infection.
276	A CRITICAL ROLE FOR CD63 IN HIV INFECTION OF MACROPHAGES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 276) Syed Hasan, H Chen, D Rojo, J Von Lindern, N Liburd, M Ferguson, and W O'Brien Association of CD63 and CD4/CCR5 in TEM appears to be important for HIV infection, and is especially critical when expression of CD4 and CCR5 is limiting, as in primary macrophages. However, siRNA-induced down-regulation of CD63 in high CD4 cells or MØ can also affect HIV susceptibility. CD63 may play a role in post-entry events, since HIV replication is inhibited in high CD4 cell lines (resistant to anti-CD63 monoclonal antibody pre-treatment) by siRNA-induced down-regulation of CD63 and by post-infection anti-CD63 monoclonal antibody treatment in MØ. Defining specific mechanisms of CD63 involvement in viral replication may identify desirable antiviral targets.
277	HIV-1 INFECTION OF UNCULTURED BLOOD DENDRITIC CELLS IS ASSOCIATED WITH EARLY SELECTIVE ENTRY OF R5 VIRUS AND A PREDOMINANTLY INFECTIOUS ROUTE OF TRANSFER TO T CELLS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 277) Paul Cameron¹, A Handley², D Baylis², A Solomon¹, N Gardner², D Purcell², and S Lewin³ mDC and pDC are, ex vivo, the most susceptible blood leukocytes for R5 but not X4 HIV infection. HIV infection is initially latent but increased viral mRNA is induced during cognate DC-T cell interactions and R5 virus is transferred to T cells. DC infection provides selection for R5 HIV in blood.
278	HIV CO-RECEPTOR USAGE MODULATE HOST GENE EXPRESSION IN CD4+ T CELLS INDUCED BY HIV INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 278) Mélissa Sirois¹, L Robitaille¹, J Fortin¹, and J Corbeil^1,2 Our data demonstrate that R5 viruses activate unstimulated CD4+ T cells to a greater extent than X4. Furthermore, X4 viruses decrease genes that inhibit apoptosis, such as FAIM3. The differences in modulation of host gene expression involved in T cell activation is initiated in accordance with the G protein coupled receptor utilized by HIV-1.
279	IMMUNOPATHOGENESIS OF X4- AND R5-TROPIC VIRUSES AMONG TREATMENT-EXPERIENCED, VIREMIC SUBTYPE C HIV-1-INFECTED ZIMBABWEANS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 279) Seble Kassaye¹, E Johnston¹, B McColgan^1,2, L Zijenah², R Machekano³, D Israelski^1,3, and D Katzenstein¹ Current practice in resource limited settings where treatment changes are not driven by viral load testing will result in prolonged viremia on ART. In this setting X4- and X4/R5-tropic viruses were common among treatment experienced subtype C HIV-1-infected patients. X4 tropism, was not, per se, associated with increased pathogeneicity, but was weakly associated with CD4 cell loss on treatment in the setting of non-suppressive ART.
280	HUMAN β-DEFENSIN-3 PROMOTES INTERNALIZATION OF THE HIV CO-RECEPTOR CXCR4 WITHOUT CALCIUM SIGNALING OR ERK-1/2 PHOSPHORYLATION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 280) Z Feng, G Dubyak, Michael M. Lederman, and A Weinberg hBD-3, an innate mucosal defense element, can provide selective blockade of the HIV co-receptor CXCR4. This novel antagonistic interaction between an innate host defense peptide and a chemokine receptor may contribute to the restriction of infection and replication by X4 tropic HIV isolates at mucosal sites of HIV entry and at submucosal lymphoid sites of HIV replication.
281	A NOVEL 24-BP DELETION IN THE CODING REGION OF CCR5: PREVALENCE IN 178 MOTHER/CHILD PAIRS AND 93 SERODISCORDANT COUPLES IN KIGALI, RWANDA Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 281) C Masquelier¹, J Servais¹, François Roman¹, S Tuyizere², C Omes³, O Courteille^2,3, E Karita⁴, S Allen⁵, J Schmit¹, and V Arendt^1,3 We report a new 24-bp deletion in the coding region of CCR5 in humans. The deletion affects highly conserved amino acids among the G-protein-coupled family. The mutation seems rare (allele frequency 0.003) and does not prevent HIV-1 infection in heterozygous individuals. However, it is likely that hCCR5Δ24 will lead to a truncated protein with impaired HIV-1 co-receptor functions and that it might influence HIV-1 transmission in Rwanda.
282	HIV REPLICATION IS INHIBITED BY THE GB VIRUS C ENVELOPE GLYCOPROTEIN E2 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 282) Susan Jung, M Eichenmueller, N Donhauser, F Neipel, B Fleckenstein, and H Reil Since we could demonstrate that GBV-C replication is not required for HIV suppression and the E2 protein is sufficient to induce the release of antiretroviral factors, our findings may result in a new HIV therapeutic approach. Even though the inhibitory mechanism is not clear, inhibition of R5 tropic HIV isolates can be explained by secretion of RANTES and decreased CCR5 surface expression.
Session 60—Poster Abstracts Viral Reservoirs: Monocytes/Macrophages
283	DIVERSE GENOTYPES AND PHENOTYPES OF HIV-1 STRAINS IN BLOOD MONOCYTES: REPLICATING VIRUSES WITH EFFECTIVE ART Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 283) R Zioni¹, Y Xu¹, H Zhu¹, N Llwellyn¹, C Wilcox¹, T Andrus¹, L Corey², and T Zhu^1,2 HIV-1 in blood monocytes evolved significantly, which could lead to observed heterogeneous genotypes and phenotypes in blood monocytes. Sole infection of macrophages by HIV-1 in monocytes suggests an independent dissemination of HIV-1 in monocytes-macrophage lineages in vivo. New drugs targeting HIV-1 in monocyte-macrophage lineages may be required.
284	PHENOTYPE OF HIV-1 STRAINS DERIVED FROM BLOOD MONOCYTES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 284) Younong Xu¹, C Wilcox¹, H Zhu¹, A Van’t Wout¹, T Andrus¹, L Stamatatos¹, J Mullins¹, M McElrath², L Corey², and T Zhu^1,2 These findings indicate that blood monocytes could harbor viruses with multiple phenotypes at early or late stages of HIV-1 infection. The majority of these viruses could infect both macrophages and CD4+ T cells efficiently. However, some monocyte HIV-1 strains only infected macrophages, indicating an independent role of monocyte-macrophage lineages in the persistence of HIV-1 infection.
285	CONTROLLING THE VIRUS OUTPUT VIA UROKINASE RECEPTOR AND CD18/CD11b INTEGRIN Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 285) Guido Poli¹, C Elia¹, N Sidenius¹, F Blasi¹, C Laudanna², and M Alfano¹ RhoA-dependent cytoskeleton rearrangement and intracellular vesicles formation may be related to virion budding and entrapment in intracytoplasmic vacuoles. This is the first report linking integrin activation to a negative control of HIV replication, at least in cells of the monocyte/macrophage lineage.
Session 61—Poster Abstracts Mechanisms of Pathogenic and Nonpathogenic Infection
286	NATURAL NON-PATHOGENIC SIV INFECTION OF SOOTY MANGABEYS IS ASSOCIATED WITH RAPID VIRUS TURNOVER AND SHORT IN VIVO LIFESPAN OF INFECTED CELLS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 286) S Gordon¹, Richard Dunham¹, J Engram¹, I Pandrea², B Lawson¹, D Sodora³, S Staprans¹, A Perelson⁴, G Silvestri¹,and H Lee⁴ Similar to pathogenic HIV/SIV infections, natural SIV infection of sooty mangabeys is characterized by rapid viral turnover, the vast majority of viral replication occurring in short-lived infected cells. These findings indicate that the AIDS resistance of SIV-infected sooty mangabeys is unlikely to be related to a longer lifespan of infected cells.
287	MOLECULAR MECHANISMS OF LONG-TERM SURVIVAL IN SIV-INFECTED RHESUS MACAQUES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 287) Michael George, E Reay, C Miller, and S Dandekar Patterns of host gene expression indicate that natural suppression of disease progression in SIV infection may be dependent on the ability to control inflammatory processes and reduce the level of local cytotoxicity, apoptosis, and destruction of the GALT microenvironment. However, although the reduction of these pathologies may increase overall survival, chronic impairment of epithelial cell/enterocyte function appears to be independent of viral suppression and thus may ultimately contribute to progression to AIDS, even in LTNP.
288	HIV-1-INFECTED LONG-TERM NON-PROGRESSORS DISPLAY NORMAL CD4+ T CELL LEVELS AND REDUCED IMMUNE ACTIVATION AND INFLAMMATION WITHIN THE INTESTINAL MUCOSA Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 288) Sumathi Sankaran¹, M George¹, M Guadalupe¹, E Reay¹, T Prindiville¹, J Flamm², and S Dandekar¹ Our findings indicate that, in contrast to patients with high viral load, LTNP maintain both peripheral and CD4+ T-cell levels and control immune and inflammatory responses. Down-regulation of genes associated with digestive and barrier functions highlight the insidious effects of HIV-1 infection that occur in all patients in all stages of disease progression, regardless of their ability to control viral replication.
289	CLOSE RELATIONSHIP BETWEEN PEAK VIRAL LOAD AND CD4+ T CELL DEPLETION IN ACUTE SHIV INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 289) Miles Davenport¹, L Zhang¹, J Shiver², D Casimiro², R Ribeiro³, and A Perelson³ This analysis allows us to predict the level of viral load control required to prevent significant CD4+ T cell depletion in acute SHIV infection. Thus, it allows us to understand how different interventions such as vaccination, passive antibody therapy, or early ART can program the long-term outcome of infection. Further studies are required to establish whether the simple relationship we found for SHIV infection exists between viral load and CD4+ T-cell depletion in HIV.
290	HIGHER PRE-SEROCONVERSION VITAMIN E LEVELS ARE ASSOCIATED WITH MORE RAPID HIV-1 DISEASE PROGRESSION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 290) Susan Graham¹, J Baeten¹, B Richardson¹, D Bankson¹, L Lavreys¹, J Ndinya-Achola², K Mandaliya³, J Overbaugh⁴, and R McClelland¹ Higher pre-seroconversion vitamin E levels were associated with both higher HIV-1 RNA viral set point and mortality. The association between vitamin E level and mortality remained significant after adjustment for HIV-1 RNA viral set point, suggesting an effect independent of set point viral load. The mechanism by which vitamin E affects disease progression is unknown, but vitamin E can increase CCR5 expression and thereby influence HIV-1 susceptibility. Although vitamin E has been considered beneficial in HIV disease, our findings indicate that higher vitamin E levels prior to HIV-1 acquisition may be associated with increased viral replication and mortality.
291	THE NEF-VIF CONNECTION IN LONG-TERM HIV-1-INFECTED HEMOPHILIACS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 291) Elisa Vicenzi¹, T Coradin¹, A De Rosa¹, F Canducci¹, M Clementi¹, S Ghezzi¹, G Poli¹, and C Bovolenta² LTNP-4 is a single LTNP who is in a healthy condition after >20 years of infection. Her PBMC-associated HIV DNA showed hypermutated nef sequences suggestive of alterations of the Vif-APOBEC axis. This Vif indeed is characterized by mutations that render the viral protein either unstable or poorly expressed.
292	EFFECTS ON HUMAN B LYMPHOCYTES OF HIV-1-ASSOCIATED HOST CD40 LIGAND Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 292) Genevieve Martin, J Roy, C Barat, C Gilbert, and M Tremblay Altogether the data gathered from this series of investigations suggest that incorporation of host-encoded CD40L in HIV-1 might play a role in the described B-cell abnormalities seen in infected individuals.
Session 62—Poster Abstracts Virus Transmission and Evolution
293	LACK OF EVIDENCE OF TRANSMISSION OF HIV-1 STRAINS BETWEEN CHRONICALLY INFECTED SEXUAL PARTNERS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 293) Mary Campbell, K Wong, D Nickle, S Hawes, G Gottlieb, N Kiviat, and J Mullins The lack of evidence for transmission of HIV-1 strains between chronically infected sexual partners supports the hypothesis that high numbers of uninfected target cells, low viral load, and absence of ART increases susceptibility to superinfection. This furthers our understanding of the mechanism of superinfection, in that these data suggest that viruses can infect only when there are available target-cell niches.
294	LONGITUDINAL ANALYSIS OF HIV-1-SPECIFIC CTL AND VIRAL SEQUENCES DEMONSTRATES SUPERINFECTION BY A CTL-EVADING HIV-1 STRAIN IN A HIV-1-INFECTED SUBJECT Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 294) Thomas Harrer¹, M Bäuerle¹, P Chaplin², J Vollmar², J Hain², S Bergmann¹, K Eismann¹, M Rittmaier¹, S Müller¹, and E Harrer¹ Because superinfection with HIV-1 variants evading CTL recognition can jeopardize immunologic control of HIV-1, infected individuals should avoid unsafe sex. Low-level vaccine-primed CTL could not prevent superinfection, however, our data suggest that they contributed significantly to the subsequent viral control.
295	THE HYPER-VARIABLE V1V2 DOMAIN OF ENVELOPE gp120 IS A DETERMINANT OF NEUTRALIZATION SENSITIVITY IN SUBTYPE C HIV-1 HETEROSEXUAL TRANSMISSION PAIRS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 295) Rong Rong¹, B Li¹, J Mulenga², S Allen¹, J Blackwell¹, B Korber³, and C Derdeyn¹ Changing the topology of the V1V2 domain has a dramatic influence on neutralization sensitivity in the context of the newly transmitted Env. This implies that acquisition of length and glycosylation in V1V2, which appears to be selected against during heterosexual transmission of subtype C, is one of multiple mechanisms of escape from neutralizing antibodies during chronic infection.
296	DIFFERENTIAL EVOLUTION OF PRO, POL, AND ENV IN PATIENTS RECENTLY INFECTED WITH HIV-1 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 296) Mary Kearney^1,2, F Maldarelli¹, A Li¹, J Margolick³, A Wiegand¹, V Rao², J Mellors⁴, J Coffin¹, and S Palmer¹ The rates and patterns of HIV-1 diversification and divergence within individuals vary by gene: env>>pro>pol. Diversity in env can drop dramatically, indicating strong genetic bottlenecks, whereas diversity in pro and pol increase steadily. These differences are likely driven by varying selective pressures rather than differences in the underlying mutation rate. The predominance of nonsynonymous changes in pro and env imply positive selection to escape CTL and antibody pressure, respectively. The rarer occurrence of nonsynonymous changes in pol suggests less immune pressure or purifying (negative) selection.
297	HIGHLY DIVERGENT VIRAL LINEAGES IN BLOOD DNA APPEAR FREQUENTLY DURING SUPPRESSIVE THERAPY IN PERSONS EXPOSED TO SUPERINFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 297) J Marcus¹, J McConnell¹, T Liegler², L Chow², J Javier², C Kreis¹, L Bragg¹, J Krek¹, and Robert Grant¹ The viral variants that appeared in PBMC DNA of these persons on suppressive therapy are much more divergent (and polyphyletic) than expected from endogenous evolution and archiving of previously circulating variants. Among chronically infected individuals, the finding of frequent limited superinfection in DNA populations during suppressive therapy contrasts markedly with the rarity of systemic superinfection during which plasma RNA populations are overgrown by new variants of HIV-1. The mechanisms that make systemic superinfection rare (as expressed in plasma RNA populations) in chronic infection may not prevent limited superinfection of DNA populations.
Session 63—Poster Abstracts Cellular and Innate Immune Reponses
298	ANTI-HIV-1-SPECIFIC RESPONSE AND IN VITRO SUPPRESSIVE ACTIVITY MEDIATED BY CD8+ T CELLS FROM HIV CONTROLLERS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 298) C Lacabaratz¹, Asier Sáez-Cirión², O Lambotte³, A Urrutia¹, P Versmisse², J F Delfraissy³, M Sinet¹, G Pancino², and A Venet¹ Our results show that CD8+ T cells from HIV controllers exhibit a potent suppressive activity of HIV-1 replication and a high and wide specific response. This strongly suggests a role for CD8+ T cells in the spontaneous control of viral replication, either by innate or adaptive responses.
299	CHANGE IN CD8 ACTIVATION MARKERS CORRELATES WITH WEEK 48 CD4+ T CELL INCREASE AMONG PREVIOUSLY NAÏVE INDIVIDUALS RECEIVING HAART, BUT THE EFFECT IS STRONGLY MODIFIED BY BASELINE THYMIC SIZE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 299) Rodriguez Benigno¹, R Pollard², J Spritzler³, G Robbins⁴, R Gandhi⁴, R Matining³, D Asmuth², A Landay⁵, M Lederman¹, R Kalayjian^1,6, and the ACTG 384 and A5007s Study Teams The magnitude of change in CD8 T cell activation is negatively correlated with CD4 cell replenishment 48 weeks after HAART, but this association is apparent only in subjects with larger thymuses. This differential relationship is stronger for memory, relative to total CD4 cells, and suggests distinct mechanisms underlying T-cell regeneration according to thymic output. The significance of these associations among subjects with viral suppression also supports an independent contribution of immune activation to T-cell reconstitution.
300	SPONTANEOUS CONTROL OF HIV-1 FOLLOWING PERINATAL INFECTION IS ASSOCIATED WITH IL-2 SECRETION BY CD8+ T CELLS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 200) Margaret Feeney^1,2, B Goudy¹, J Steel-Duncan³, A Rathod¹, S Burchett², K McIntosh², S Pelton⁴, M St John⁵, C Christie³, and B Walker¹ Genetic factors play a major role in successful immune containment of HIV, with certain class I HLA molecules strongly over-represented among controller subjects. The presence of HIV-specific IL-2 production by CD8 T cells in controllers suggests that genetic and immunologic determinants of viral control are likely to be interdependent, and may be mediated through qualitative differences in the T cell response to epitopes presented by “beneficial” HLA molecules.
301	PROLIFERATION, ACTIVATION, EXPANSION, AND CYTOTOXIC ACTIVITY OF GASTROINTESTINAL CD8+ T CELLS DURING PRIMARY HIV-1 INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 301) Saurabh Mehandru¹, M Poles^1,2, K Tenner-Racz³, A Shet¹, P Jean-Pierre¹, P Racz³, and M Markowitz¹ During primary HIV infection, there is a significant increase in gastrointestinal tract CD8+ T cells, most prominent in the effector compartment. An activated, proliferating phenotype of these cells, combined with increased expression of effector molecules such and perforin and granzyme may indicate an important role of these cells in the pathogenesis of primary HIV infection.
302	INHIBITORY MHC CLASS I-SPECIFIC RECEPTOR EXPRESSION IMPAIRS HIV-SPECIFIC CD8+ T LYMPHOCYTE FUNCTIONS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 302) P Masdehors¹, D Marsac¹, I Liberman¹, C Rapp², J P Viard³, and Marie-Lise Gougeon¹ We provide evidence that chronic HIV infection induces an up-regulation of MHC class I inhibitory receptors on CD8 T cells, leading to the impairment of effector functions. Since HIV-specific T cells highly express CD85j, and the expression of iNKR is associated with late stages of differentiation, we propose that the negative control exerted by these receptors may contribute to the alterations of CTL functions and to viral escape.
303	PRESERVATION OF CD4+ ANTIGEN-SPECIFIC MEMORY CELLS CORRELATES WITH CONTROL OF VIREMIA IN SIV_mac-INFECTED MACAQUES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 303) A Valentin¹, A Von Gegerfelt¹, M Rosati¹, C Alicea¹, P Roth¹, J Bear¹, P Albert², R Ruprecht³, George N Pavlakis¹, and B Felber¹ We found preservation of central memory T cells in macaques controlling viremia. Animals infected by attenuated SIV and animals able to control virus after DNA therapeutic vaccination were shown to have high levels of antigen-specific CD4+ cells in central memory.
304	HIV-1 VPR INFECTION ALTERS DC PHENOTYPIC MATURATION, ANTIGEN PRESENTATION, AND TARGETED PRIMING OF CD8+ T CELLS: VIRAL STRATEGY OF HOST IMMUNE EVASION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 304) Biswanath Majumder¹, E Schafer¹, M Janket¹, N Venkatachari¹, J Kan-Mitchell², C Rinaldo Jr.¹, and V Ayyavoo¹ Together, these results illustrate a new role of Vpr in ongoing immune evasion by altering DC biology and functional competence of CD8+ T cells, and therefore suggest Vpr as a potential target for developing newer ART.
305	INTERLEUKIN 18 AND HIV-1 INFECTION IN ADOLESCENTS AND ADULTS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 305) Wei Song Consistent with all earlier observations, serum IL-18 levels closely correlate with adverse events or outcomes related to HIV-1 infection.
306	IMPAIRED NAÏVE AND MEMORY B CELL RESPONSES TO TOLL-LIKE RECEPTOR-9 STIMULATION IN HIV INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 306) Wei Jiang, S Sieg, R Mohner, C Harding, and M Lederman Our results suggest that decreased responsiveness to Toll-like receptor-9 (TLR9) stimulation among both naïve and memory B cells from HIV-infected persons could contribute to increased susceptibility to bacterial infection and generalized immune dysfunction in HIV infection.
307	SINGLE NUCLEOTIDE POLYMORPHISM IN THE PROMOTER OF PKR SUPPORTS INNATE HIV-1 RESISTANCE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 307) C Lodrini¹, Giulia Morsica¹, A Galli¹, A Castagna¹, R Finazzi¹, S Ghezzi¹, A Lazzarin¹, G Bianchi², and S Bagaglio¹ These results suggest that homozygosity T/T at position -168 of PKR-promoter could exert a protective effect against HIV-1 infection, whereas heterozygosity C/T at the same position could be associated with increased risk of HIV infection.
Session 64—Poster Abstracts Host Cell Activation: Impact on Replication
308	T LYMPHOCYTE PROLIFERATION AFTER ACTIVATION IS CRITICAL FOR OPTIMAL HIV REPLICATION AND FOR DRUG TARGETING Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 308) Andrea Foli, M Maiocchi, J Lisziewicz, and F Lori The results demonstrate a correlation between HIV replication and cell proliferation, but not cell activation. Drugs preventing cell cycle progression from G1 to S phase confirmed that HIV replication can be uncoupled from cell activation but not cell proliferation. The results represent a model for novel drug targeting.
309	HIV INFECTION OF QUIESCENT CD4+ T CELLS FOLLOWED BY IMMEDIATE ACTIVATION RESULTS IN REDUCED VIRAL REPLICATION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 309) Dimitrios Vatakis, G Bristol, T Wilkinson, S Chow, and J Zack Stimulation immediately following infection of quiescent CD4+ T cells results in very poor rescue of productive infection. This suggests that the inhibitory factors present in these cells act immediately on early HIV life cycle intermediates, and are largely irreversible. In addition, since post-stimulated cells that produced viral protein following activation did not progress through a second incorporation of BrDU, the provirus in these cells does not replicate by cell division. Further studies are warranted to examine the exact mechanisms involved in these events, including the potential role of APOBEC3G.
Session 65—Poster Abstracts Impact of Antiretroviral Therapy on Virus and Host
310	PARTIAL NORMALIZATION OF THE ACTIVATED IMMUNE RESPONSE IN LYMPH NODES OF HIV-INFECTED INDIVIDUALS UNDER ART Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 310) Simone Ehrhard¹, M Wernli¹, M Battegay², F Gudat², G Kaufmann², G Pantaleo³, G Rizzardi⁴, and P Erb¹ Under ART normalization of follicular hyperplasia of germinal centers, reduction of the CD8 T-cell number and recovery of FDC indicate a return to normal immune activation in lymph node similar to that in HIV individuals. The increase of the IL-7αR indicates that interleukin -7 (IL-7), known to impair cell mediated immunity, is down-regulated. Reduced dysregulation of apoptosis is manifest by the up-regulation of bcl-2 in the mantle zone, of caspase-3 in the sinus, of Fas within germinal centers and of FasL interfollicularly. Hence, the highly activated immune response and the CD8 CTL-activity present in lymph nodes of untreated patients tend to normalize under ART.
311	HAART BLOCKS THE ACCELERATED EROSION OF TELOMERES INDUCED BY HIV INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 311) B Unryn, L Bestilny, K Riabowol, and M John Gill HAART blocks the accelerated telomere erosion seen in the circulating component of the immune system during HIV infection. However, it does not restore telomere sequences previously lost, indicating that repopulation of PBMC from progenitor cells or activation of telomerase does not restore replication potential. Preservation of telomere length should be considered as a potential advantage favoring earlier HAART use.
312	INFLUENCE OF BLIPS OF VIRAL LOAD DURING HAART ON CONTROL OF VIRAL REPLICATION AFTER DISCONTINUING HAART Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 312) Pedro Castro, A López, M Plana, C Gil, R González, A Vilella, E Fumero, T Pumarola, J Gatell, and F García Early stage HAART-treated patients with blips controlled viral replication after interruption of treatment more poorly, although it did not influence the drop in CD4+ T cells after 6 months off HAART. Repeated immunological stimuli with commercial vaccines (a total of 195 stimuli in 13 patients) do not influence in the rebound after stopping HAART.
313	SOUTH AFRICAN PATIENTS HAVE DECREASED CD4+ T CELL REPLENISHMENT AND PERSISTENTLY ELEVATED T CELL ACTIVATION DURING HAART COMPARED WITH NORTH AMERICAN PATIENTS, DESPITE BETTER VIROLOGIC RESPONSES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 313) Gopala Yadavalli¹, M Lederman¹, M Lisgaris¹, W Stevens², I Sanne², P Cahn³, A Landay⁴, S Schnittman⁵, T Kelleher⁵, and B Rodriguez¹ Despite better virologic response, South African subjects exhibited smaller total and naïve CD4 cell count increases in response to an initial HAART regimen, compared with North Americans. These differences were accompanied by strikingly higher levels of CD4 and CD8 activation among South Africans, which persisted through 48 weeks of follow-up and correlated inversely with CD4+ T cell count at most time points. Heightened immune activation, perhaps reflecting increased cellular turnover or persistence in tissue, may underlie the disparity in HAART-associated immune reconstitution seen in certain patient groups.
314	HIV PROTEASE INHIBITOR BLOCKS GP120-INDUCED CD4 T-CELL DEATH BY PREVENTING MITOCHONDRIAL DESTABILIZATION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 314) Stacey Vlahakis, G Bren, S Trushin, D Schnepple, and A Badley The HIV protease inhibitor NFV blocks gp120/CXCR4-mediated CD4 T-cell apoptosis and prevents mitochondrial membrane destabilization, but does not alter normal CD4 T-cell chemotactic function. Therefore, HIV protease inhibitors can protect CD4 T cells from gp120-mediated cell death, as well as block HIV replication.
Session 66—Poster Abstracts Molecular Epidemiology
315	ESTIMATION OF HIV-1 SUBTYPE B MIGRATION WITHIN EUROPE AND BETWEEN EUROPE AND THE UNITED STATES BASED ON PHYLOGENETIC ANALYSES OF 1101 SEQUENCES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 315) Dimitrios Paraskevis¹, A Rambaut², G Magiorkinis³, A Hatzakis³, A M Wensing⁴, D Van De Vijver⁴, C Boucher⁴, and A M Vandamme¹ This is the first study estimating migration events between HIV-1 subtype B sequences sampled from Europe (Israel included) and the United States, based on phylogenetic inference. Our study provides an insight into how the epidemic spreads within Europe and between Europe and the United States. According to the estimated migration matrices within Europe, certain European countries show a high exporting, while others show a high importing HIV-1 migration. In all, there is a net HIV-1 subtype B import from the United States to all European countries. Our findings contribute to a better understanding of the HIV-1 epidemic spread in Europe, assisting better prevention strategies.
316	INCREASING AND UNUSUAL GENETIC DIVERSITY OF HIV-1 IN THE UK Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 316) Robert Gifford¹, T De Oliveira², A Rambaut², R Myers¹, C Gale¹, D Dunn³, R Shafer⁴, A M Van Damme⁵, P Kellam¹, D Pillay^1,6, and UK Collaborative Group on HIV Drug Resistance Ongoing generation of HIV-1 genetic diversity via recombination and sequence drift is diluting the epidemiological content of existing subtype definitions and eroding the distinctions between some hitherto well-defined subtypes. Continuing to use the present system of subtype classification for epidemiological and clinical purposes will require a critical understanding of the methodologies used in order to appreciate the possible sources of error and misclassification. Novel surveillance and classification systems should be developed for further tracking the dissemination of HIV-1 genetic variants.
317	THE MOLECULAR EPIDEMIOLOGY OF A HETEROSEXUAL SUBTYPE B HIV EPIDEMIC: THE LATEST RESULTS FROM THE CARIBBEAN Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 317) Jean Carr¹, Y Nadai², L Eyzaguirre², M Charurat¹, A Sill¹, N Jack³, F Cleghorn⁴, W Pape⁵, E Guerrer⁶, and W Blattner¹ These are the first full length genome sequences from the Caribbean since the early 1980’s. The strains from these 4 countries were overwhelmingly subtype B. The genetic isolation of the TT strains from the mid-1990’s is no longer visible in the most recent samples, though the majority of strains from TT still retain the earlier signature in V3. Glycosylation differences between the Caribbean envelopes and those in North America may relate to natural selection of the Caribbean virus for heterosexual transmission.
318	MOLECULAR EPIDEMIOLOGY OF HIV-1 IN OYO STATE, NIGERIA: CRF02AG DOES NOT CONSTITUTE THE MAJORITY OF CIRCULATING HIV-1 STRAINS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 318) Jean-Louis Sankale¹, S Langevin¹, G Odaibo², D Olaleye², and P Kanki¹ This is the first in depth analysis of HIV variability at the level of a state in Nigeria. It uncovered a significant level of viral heterogeneity, a geographical difference in subtype distribution, and demonstrated that CRF02AG does not account for the majority of circulating strains. Vaccine development strategies need to take these findings into account and incorporate subtype G.
319	A NIGERIA-SPECIFIC CLUSTER OF HIV-1 SUBTYPE G IS SUSTAINED IN FULL-LENGTH GENOME SEQUENCING Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 319) Seema Meloni¹, J L Sankale¹, G Odaibo², D Olaleye², and P Kanki¹ This the first report containing data on full-length G' sequences from Nigeria. Given that previous reports had indicated that a majority of sequences from this region of the world were recombinant viruses, we were surprised to find that our full-length G' viruses maintained the distinct sequence across the length of the entire genome. We believe our full-length data will be useful in our continued efforts to track and understand the HIV-1 epidemic in Nigeria and to help in the development of vaccines appropriate for the sub-region.
320	HIV-1 GROUP N: EVIDENCE FOR ONGOING TRANSMISSION IN CAMEROON Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 320) J Yamaguchi¹, R Coffey¹, A Vallari¹, P Bodelle¹, D Mbanya², N Ndembi², L Kaptue², C McArthur³, S Devare¹, and Catherine Brennan¹ This report documents the first case of horizontal transmission of HIV-1 group N. In addition, a second case of linked infections is suggested by the close relationship of the viruses present in the DJO specimens. Together these results indicate there is ongoing transmission of group N in Cameroon.
321	GENETIC ANALYSIS OF HIV-1 STRAINS CIRCULATING IN THE RURAL AREAS OF EASTERN CAMEROON Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 321) Frank Konings¹, G Haman¹, Y Xue², M Urbanski¹, K Hertzmark¹, S Burda¹, and P Nyambi¹ All isolates studied from the rural villages of Eastern Cameroon are predicted to be R5-tropic with large numbers of non-recombinant strains (56%), second-generation recombinants (40%), and A outliers in env (24%). Together with the drug-resistance information and V3-loop composition these data are essential for the design of future diagnostics, drugs, and vaccines targeted at this part of Africa.
322	AN OUTBREAK OF INFECTION DUE TO HIV-1 SUBTYPE CRF07_BC AMONG INTRAVENOUS DRUG USERS IN TAIWAN Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 322) S Y Chang, C C Hung, S C Chang, M Y Chen, and Hsin-Yun Sun Our findings indicate that the recent outbreak of HIV-1 infection among persons with IDU may have resulted from a clonal expansion of CRF07_BC virus and this outbreak has not been spread to other risk groups in Taiwan.
323	SELECTIVE ADVANTAGE OF HIV-1 SUBTYPE C LTR IN INTER-SUBTYPE RECOMBINATION IN VIVO Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 33) Yutaka Takebe The predominance of HIV-1 subtype C LTR in Dehong Unique recombinant forms suggests the biological advantage of LTR of subtype C over that of subtype B in in vivo recombination event. The HIV-1 subtype C LTR is known to show stronger transcriptional activity upon activation than LTR of other subtypes. The higher replicative potential of subtype C due to 3 NFκB configuration may explain the apparent selective advantage of subtype C LTR observed in the present study.
324	INTER-CRF RECOMBINANTS: A NEW CLASS OF HIV-1 RECOMBINANTS AND ITS EPIDEMIOLOGICAL IMPLICATIONS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 324) Yutaka Takebe Mixing of different lineages of HIV-1 strains in a highly exposed population leads to the evolution of new forms of HIV-1 recombinants and even the second-generation recombinants between previously established CRF. In the present study, we identified 2 novel classes of inter-CRF recombinants (ICR) between CRF07_BC and CRF08_BC in Yunnan Province (China) and between CRF07_BC and CRF01_AE in Yangon (Myanmar). This suggests the dynamic relationship of the epidemic in Asia. We propose to designate these new recombinants as ICR01_0708 and ICR02_0701.
325	THE DISTRIBUTION OF HIV-1 RECOMBINATION BREAKPOINTS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 325) Jun Fan¹, M Negroni², and D Robertson¹ Our results indicate that positive selection is having an impact on HIV-1 recombinant structures in infected individuals. A correlation was observed between recombination prone regions and predicted positively selected regions in support of this hypothesis. The significance of these results for unique and circulating recombinant forms will be discussed.
326	EMERGENCE OF X4 USAGE AMONGST HIV-1 SUBTYPE C: EVIDENCE FOR AN EVOLVING EPIDEMIC IN SOUTH AFRICA Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 326) Bridgette Connell, K Michler, A Capovilla, F Venter, W Stevens, and M Papathanasopoulos We report the highest percentage of CXCR4-usage amongst primary isolates from HIV-1 subtype C infected AIDS patients in South Africa. These results imply that the frequency of HIV-1 subtype C CXCR4-utilizing viruses may be increasing with time, as was previously documented in the CRF01_AE epidemic. The emergence/evolution of CXCR4-usage amongst HIV-1 subtype C may have profound implications for viral pathogenesis, disease progression and future use of CCR5 antagonists as antiretroviral agents.
327	HIGHER PREVALENCE OF CXCR4 CO-RECEPTOR USE IN SUBTYPE D HIV-1 COMPARED TO OTHER SUBTYPES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 327) Wei Huang¹, S Eshleman², S Fransen¹, J Toma¹, E Paxinos¹, T Wrin¹, J Whitcomb¹, N Parkin¹, J Jackson², C Petropoulos¹, and the HIVNET 012 Study Team Among ARV-naïve Ugandan women, subtype D viruses have a dramatically higher prevalence of CXCR4 utilization than subtype A viruses. In a larger sample set, use of CXCR4 was similar in subtype A, C, F, CRF01_AE or G (9 to 18%) compared to subtype B samples (~20%), but was significantly higher in subtype D samples (~50%).
328	MOLECULAR PHYLOGENY OF FULL-LENGTH HIV-1 SUBTYPE C GENOMES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 328) Christine Rousseau¹, G Learn¹, Y Liu¹, S Chetty², P Kiepiela², P Goulder^3,4, C Brander⁴, B Korber⁵, B Walker⁴, and J Mullins¹ Subtype C sequences demonstrated geographic clustering, probably due to a low number of founder viruses in South America, India, and the Horn of Africa. Similar to Botswana HIV-1 sequences, South Africa HIV-1 sequences formed several distinct subclusters, suggesting several founders. However, the sequences from Botswana had greater diversity. The clusters were not maintained in subgenomic regions and several sequences appear to be intra-subtype recombinants. Vaccine designs specific for the Southern Africa region will need to be protective against a highly diverse viral population.
Session 67—Poster Abstracts Neuropathogenesis: Virology and Immunology
329	HIV-1 TROPISM FOR THE CENTRAL NERVOUS SYSTEM: BRAIN-DERIVED ENVELOPE GLYCOPROTEINS WITH LOWER CD4 DEPENDENCE AND REDUCED SENSITIVITY TO A FUSION INHIBITOR Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 329) Julio Martin-Garcia¹ and F Gonzalez-Scarano² Our results confirm an increased affinity for CD4 of brain-derived envelopes that may have originated from in vivo adaptation to replication in microglial cells. More interestingly, we note the presence of envelopes significantly less sensitive to a fusion inhibitor in the brain vs the spleen of an untreated, HIV-1-infected individual. Changes in the interaction with CD4 but not CCR5, or the specific polymorphism found in HR2 in these brain sequences, may be related with the observed phenotypic differences.
330	IDENTIFICATION OF RESIDUE 308 IN THE V3 LOOP OF HIV GP120 AS A BRAIN SIGNATURE POSITION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 330) Elaine Thomas^1,2, R Dunfee^1,2, D Bogdan³, J Stanton³, K Kunstman³, S Wolinksy³, and D Gabuzda^1,2 Analysis of HIV Env from brain and lymphoid tissue from 4 patients with HAD identified P308 as a brain signature, which may reflect genetic adaptation to replication in macrophages/microglia or reduced immune selection pressures within the central nervous system.
331	CSF PLEOCYTOSIS IS ASSOCIATED WITH VIRAL TRAFFICKING FROM BLOOD INTO CNS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 331) Hai Shao¹, D Smith¹, J Moreno¹, S Letendre², P Jordan¹, J Wong³, C Ignacio¹, D Richman⁴, S Frost², and R Ellis² Phylogenetic studies of HIV-1 viral isolates in paired blood and CSF revealed evidence of viral trafficking during CSF pleocytosis. These findings are consistent with the view that CSF is a virologically dynamic site that reflects changing interactions between extra- and intra-neural compartments. This is linked, in part, to changes in therapy and may explain why studies of CSF viral genetics do not always find evidence of compartmentalization. Further characterization of blood–CSF interactions may assist in evaluating the potential utility of CSF as a marker of virologic events in brain parenchyma, where ongoing viral replication may trigger neural injury.
332	ROLE OF CCR3 IN CNS HIV-1 INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 332) Lokesh Agrawal and D Strayer Since CCR3 and CCR5 are expressed in microglia cells, therapy targetting both may be useful in CNS AIDS. Thus, recombinant SV40 viruses of both the molecules are being tested for their ability to infect purified microglia cells and macrophages, and protect them from HIV infection. Utilization of CCR3 by these HIV-1 isolates and their susceptibility to inhibition by siRNA and ScFv in primary brain microglia/macrophages may both help clarify the role of CCR3 as a coreceptor in CNS establishing HIV-1 and provide new avenues for therapeutic manipulation.
333	ANTI-HIV CYTOTOXIC T LYMPHOCYTES IN CEREBROSPINAL FLUID AND PERIPHERAL BLOOD OF IMMUNE CONTROLLERS OF PLASMA VIREMIA Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 333) S Kalams, K Brady, B Simmons, J Conrad, S Lorey, S Montgomery, J Nicotera, and David W Haas Epitope-specific CD8+ T cells can be readily expanded from CSF of asymptomatic HIV-infected individuals, even without CSF pleocytosis. Anti-HIV CTL responses may play an important role in controlling HIV replication in the central nervous system among individuals with immunologic control of plasma viremia without ART.
334	DEFINING PATHOGENIC PATHWAYS FOR MURINE HIV-1 ENCEPHALITIS IN IMMUNODEFICIENT MICE THAT REFLECT DEFICITS IN ADAPTIVE IMMUNITY AND NK CELL FUNCTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 334) Santhi Gorantla, E Miller, H Klasek, H Dou, J Morehead, H Gendelman, and L Poluektova Loss of both adaptive immunity and NK cell activities defines the fingerprint of HIVE and affects the levels of MDM function, migration, neuroinflammation, and neuronal loss.
335	COPAXONE REGULATION OF INNATE AND ADAPTIVE IMMUNITY INDUCES SUPPRESSION OF NEUROINFLAMMATION AND ELICITS NEURONAL PROTECTION IN MURINE MODELS OF HIV-1 ENCEPHALITIS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 335) Santhi Gorantla¹, L Poluektova¹, H Klasek¹, L Walters¹, J Nelson¹, H Dou¹, T Ikezu¹, D Volsky², M Boska¹, and H Gendelman¹ Cop-1 regulates both innate and adaptive immune responses in experimental models of HIVE and shows promise for treatment of human disease.
336	ACTIVATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-γ SUPPRESSES HIV-1 REPLICATION IN BLOOD AND BRAIN IN AN ANIMAL MODEL FOR HIV-1 ENCEPHALITIS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 336) Raghava Potula, B Knipe, J Liebhart, K Schall, H Dou, and Y Persidisky These results indicate that PPAR-γ stimulation leads to effective suppression of HIV-1 replication in blood lymphocytes and brain macrophages. Our findings suggest that the anti-viral properties of orally administered PPAR-γ agonists offer new strategies for therapeutic intervention in HIV-1 encephalitis and systemic infection.
337	HIV-1-INFECTED OR IMMUNE-ACTIVATED MACROPHAGES REGULATE SDF-1 PRODUCTION BY HUMAN ASTROCYTES THROUGH IL-1β Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 337) Hui Peng, N Whitney, N Erdmann, A Ghorpade, and J Zheng These observations provide evidence that IL-1β, from HIV-1-infected and immune-activated macrophages, serves an essential role in macrophage mediated SDF-1 production from astrocytes.
338	ANTI-HIV-1 AND ANTI-APOPTOTIC EFFECTS OF D-ALA-PEPTIDE T-AMIDE IN HUMAN MACROPHAGES AND IN A NEURONAL CELL LINE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 338) Michela Pollicita¹, M Ruff², M Polianova², C Pert², A Ranazzi¹, C Perno¹, and S Aquaro¹ The mechanisms of DAPTA inhibition may include suppression of HIV-1 R5 strains in the brain, direct inhibition of HIV-1 replication in M/M and containment of damage related to gp120-CCR5 binding. The development of anti HIV-1 compounds acting through new mechanisms, such as DAPTA, could be important in synergistic combination with other ART in preventing both central nervous system HIV-1 infection and the consequent neural damage.
339	IFN-γ AUGMENTS HIV PRODUCTIVE INFECTION OF ASTROCYTES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 339) Deborah Carroll-Anzinger and L Al-Harthi Pre-stimulatory cytokine signals can prime astrocytes for HIV productive infection, the extent of which depends on the astrocytic model and the nature of the cytokine used. IFN-γ specifically enhanced HIV replication in astrocytes and modulated the expression of specific chemokine co-receptors.
340	HIV-1 GAG DNA IS PRESENT IN NEURAL PROGENITORS HARVESTED BY LASER CAPTURE MICRODISSECTION FROM ARCHIVAL PEDIATRIC BRAIN Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 340) Lynnae Schwartz¹, A Dunn-Pirio², S Ryschkewitsch³, L Durham¹, L Civitello^4,5, R Hazra⁵, D Lawrence¹, and E Major¹ HIV-1 gag DNA was found in nestin+ cells harvested from archived hippocampal tissue from a vertically infected child with neuroAIDS. This finding, along with our previously reported cell culture and periventricular in situ hybridization data, provides strong evidence that neural progenitors are a target for HIV-1 infection in vivo. HIV-1-infected neural progenitors have now been found in 2 anatomic regions of the pediatric brain, raising the possibility that HIV-1-infected neural progenitors in the developing brain may migrate from the periventricular region to the hippocampus. Because neural progenitors are critical for brain development and response to injury, HIV-1 infection of progenitors within the hippocampus might adversely affect those functions, thereby contributing to the developmental delays, and the cognitive, language, and memory impairments seen in HIV-1-infected infants and children.
341	LONG-TERM ADMINISTRATION OF ETHANOL LEADS TO INCREASED BLOOD-BRAIN BARRIER LEAKAGE DURING THE PRIMARY PHASE OF INFECTION OF MACAQUES WITH SIMIAN/HUMAN IMMUNODEFICIENCY VIRUS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 341) M. Sarah Hill, E Mulcahy, N Culley, L Gomez, N Berman, and E Stephens Taken together, these results indicate that long-term ethanol consumption leads to more extensive BBB disruption during the primary phase of infection.
342	HUMAN POLYOMAVIRUS JC CROSSES IN VITRO BLOOD-BRAIN-BARRIER BY INFECTING HUMAN BRAIN MICROVASCULAR ENDOTHELIAL CELLS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 342) Moti Chapagain, T Nguyen, S Verma, and V Nerurkar Our data indicates that cell-free JCV can infect the HBMVEC, JCV can migrate across the BBB, and based on the infection of primary human fetal glial cells, the migrated JCV is infectious. The transmigration of JCV was slow in early hours post-infection but continued to increase slowly and gradually over the next 7 days. Inability of the heat-inactivated JCV to continue to cross the BBB after 6 hours indicates that infectious JCV is essential to efficiently cross the BBB. Moreover, JCV does not employ serotonin receptors to infect HBMVEC, nor to cross the BBB, and serotonin blockers may not prevent the spread of JCV to brain cells.
Session 68—Poster Abstracts Neuropathogenesis: Biomarkers and Gene Polymorphisms
343	TNFα-308, BUT NOT IL1α-889, IL1β+3953, OR IL12β 3'UTR, IS ASSOCIATED WITH AIDS DEMENTIA COMPLEX Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 343) L Pemberton¹, E Stone², P Price², F Bockxmeer², and Bruce Brew¹ Previously 2 studies (one clinically based, the other pathology based) reported contradictory findings in relation to TNFα-308 and ADC. The present study is the largest thus far, so we suggest that the association is pathogenetically important. Indeed the association is of the same magnitude as that of the MCP-1 polymorphism. The lack of association with ApoE4 status may be related to the younger age of the ADC patients in our study. Presently the genetic risk signature for ADC appears to be TNFα-308(2,2) with BAT1(inton10)(2,x), MCP1*2578G, and ApoE (4,4), the latter being important in older patients. Other yet-to-be-determined genetic risk factors may be important. The elucidation of the genetic signature will allow the identification of patients who will require more intensive monitoring and perhaps the earlier introduction of HAART.
344	CYTOKINE GENOTYPES ESTABLISH A ROLE FOR INFLAMMATION IN ANTIRETROVIRAL TOXIC NEUROPATHY AND PREDICT AN INDIVIDUAL’S RISK Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 344) Catherine Cherry^1,2,3, A Rosenow⁴, S Wesselingh^1,2,3, I James^5,6, M French⁴, J McArthur⁷, L Lal¹, and P Price⁴ These findings support a role for inflammatory pathways in the development of ATN. If confirmed in a larger cohort, they will enable improved assessment of individual risk for ATN prior to commencing NRTI, allowing more informed treatment decisions. By facilitating an understanding of the cytokines involved in the development of ATN, these findings may also aid the development of rational immunotherapeutic strategies for this disabling problem.
345	INTERRELATIONSHIPS AMONG PLASMA AND CEREBROSPINAL FLUID COMPARTMENTAL VIRAL LOAD, CHEMOKINE/CYTOKINE LEVELS, AND HIV DRUG RESISTANCE LINKED TO COMPREHENSIVE NEUROPSYCHOLOGICAL TESTING AND NMR SPECTROSCOPY FINDINGS IN HIV-INFECTED SUBJECTS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 345) B Bush¹, Victoria A Johnson^1,2, J Hazelwood¹, E Kovacs¹, J Den Hollander¹, L Nabors¹, F Kinney¹, A Madan¹, K Netson¹, and D Benos¹ Subjects with HIV RNA ≥50 copies/mL in both plasma and CSF compartments displayed worse dementia and significantly worse neuropsychological assessment testing results, suggesting this is a clinically relevant level with respect to HIV neuropathogenesis. HIV drug resistance was seen in subjects with HIV RNA ≥50 copies/mL in both compartments, which may aggravate ongoing HIV replication, cytokine production, and neurologic deterioration.
346	THE EFFECTS OF ANTIRETROVIRAL THERAPY USE ON CEREBROSPINAL FLUID BIOMARKERS AND NEUROPSYCHOLOGICAL PERFORMANCE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 346) Scott Letendre, M Buzzell, J Marquie, M Cherner, B Ances, R Ellis, and The HNRC Group Biomarker-neuropsycholical relationships varied with the use, duration, and effectiveness of ART. In this pilot project, higher levels of total protein, a clinically available assay, were associated with worse performance in all analyses, possibly because it provides a pooled measure of many neuropathogenic proteins. Total protein may be a useful marker of NCI in a clinically important population, ART-treated individuals, and may indicate the need for intensified or adjunctive therapy.
347	NITRATION OF PROSTAGLANDIN D2 SYNTHASE IN CSF OF HIV PATIENTS WITH ACTIVE DEMENTIA OR HISTORY OF INJECTION DRUG USE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 347) Wenxue Li, R Gundry, D Esposito, D Burgess, A Barnes, J Creighton, N Sacktor, J McArthur, R Cotter, and A Nath Protein nitration due to increased production of nitric oxide as a result of oxidative stress in the brain may be an important biomarker for active HAD and injection drug abuse. Nitration of prostaglandin D2 synthase may play an important role in the pathogenesis of HAD.
348	DEFINING THE HIV-1-INFECTED MACROPHAGE PROTEOME Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 348) Pawel Ciborowski, I Kadiu, M Ricardo-Dukelow, K Bernhardt, M Fladseth, and H Gendelman The role of protein groups in circumventing macrophage innate host defense mechanisms and in secretion of factors that lead to human disease are related to these proteins dysregulations is being developed.
349	INSULIN RESISTANCE: A NOVEL MARKER OF COGNITIVE FUNCTION IN OLDER HIV+ ADULTS, THE HAWAII AGING WITH HIV COHORT Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 349) Valcour Victor¹, A Williams¹, M Watters¹, N Sacktor², O Selnes², B Shiramizu¹, R Paul³, and C Shikuma¹ We report that insulin resistance (independent of diabetes) may be a novel risk factor for cognitive impairment with particular applicability to older HIV+ patients. It is not clear that the neuropathogenesis is specific to HIV, itself; however, common pathways such as oxidative stress may make older patients particularly vulnerable to cognitive sequelae with chronic HIV. Further analyses are underway.
350	NON-SYNONYMOUS MITOCHONDRIAL DNA POLYMORPHISMS AND PERIPHERAL NEUROPATHY DURING NRTI THERAPY IN ACTG STUDY 384 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 350) Todd Hulgan¹, D Haas¹, J Haines¹, M Ritchie¹, G Robbins², R Shafer³, D Clifford⁴, A Kallianpur¹, M Summar¹, and J Canter¹ T4216C and A4917G, 2 non-synonymous mitochondrial DNA polymorphisms, were frequent among white ACTG 384 participants, and were associated with the development of peripheral neuropathy among those individuals randomized to receive ddI+d4T. These polymorphisms are known to alter amino acids in mitochondrial complex I subunits and are associated with other human neurodegenerative diseases. Further studies to validate these associations are warranted.
Session 69—Poster Abstracts Neuropathogenesis: Clinical Correlates and Observational Studies
351	THE PREDICTORS OF HIV ENCEPHALOPATHY AND OUTCOME IN HIV+ PATIENTS IN THE ERA OF EFFECTIVE THERAPY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 351) C Mussini¹, K Bhaskaran², S Walker², M Dorrucci³, C Sabin⁴, A Phillips⁴, Kholoud Porter², and CASCADE Collaboration We found an elevated risk of HIVE even at CD4 counts of 200 to 350 cells/mm³. The decrease in HIVE incidence at the same CD4 levels in the HAART era suggests a direct effect of HAART on the pathology of HIVE.
352	HIV DNA CORRELATES WITH HIV-1-ASSOCIATED DEMENTIA IN ART-NAÏVE PATIENTS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 352) Bruce Shiramizu¹, S Nidhinandana², P Sithinamsuwan², W Apateerapong¹, S Ratto-Kim^1,3, G Watt¹, K Robertson⁴, R Paul⁵, C Shikuma¹, V Valcour¹, and South East Asia Research Collaboration with Hawaii (SEARCH) High HIV DNA is a marker of HAD, not only in subjects on potent ART, as previously reported but also in ART-naïve subjects. Subjects enrolled in the SEARCH Cohort, diagnosed with HAD at baseline, showed a significant elevation in HIV DNA compared to individuals without HAD. This suggests that high HIV DNA may be a novel marker suggesting a potential role in the pathogenesis of HAD.
353	CD4 COUNT AND RISK OF HIV-RELATED COGNITIVE DYSFUNCTION IN THE ERA OF ART Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 353) Robert Paul, K Tashima, D Tate, K Coop, V Valcour, T Flanigan, and C Carpenter HIV+ patients exhibited significant cognitive impairments regardless of CD4 cell count. The results were not mediated by severity of illicit drug use, which accounted for <15% of the variance in cognitive function. These preliminary results suggest that the degree of immunosuppression may not represent a clinically useful biomarker for neurocognitive impairment in the era of ART.
354	FACTORS ASSOCIATED WITH PERSISTENT NEUROCOGNITIVE IMPAIRMENT DESPITE LONG-TERM HAART IN PATIENTS WITH HIV DEMENTIA Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 354) Valerio Tozzi, P Balestra, M Salvatori, C Vlassi, A Corpolongo, R Bellagamba, S Galgani, P Lorenzini, A Antinori, and P Narciso Although HAART was associated with improvements in cognitive functions, the impairment persisted in nearly 2 of 3 of cases, despite 3 years of HAART. Less severe impairment and prompt improvement in cognitive performance were independently associated with reversible neurocognitive impairment. Our data indicate that HAART should be initiated as soon as neurocognitive impairment is diagnosed to avoid a potentially irreversible neurological damage. Additional treatment strategies are needed in patients with persistent neurocognitive impairment.
355	CENTRAL NERVOUS SYSTEM IMMUNE ACTIVATION IS STILL PRESENT AFTER MORE THAN 4 YEARS OF EFFECTIVE HAART Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 355) Arvid Edén¹, R Price², S Spudich², D Fuchs³, L Hagberg¹, and M Gisslén¹ HAART significantly decreases intrathecal immunoactivation, but despite effective treatment for >4 years, with HIV RNA <50 copies/mL, a substantial proportion of patients continue to exhibit signs of central nervous system macrophage / microglia activation (neopterin) and intrathecal immunoglobulin production (IgG index). Whether these findings reflect ongoing low-grade viral replication in brain tissue or unspecific immunoactivation is not settled.
356	INTRATHECAL IMMUNE ACTIVATION IS REDUCED IN TREATED SUBJECTS FAILING ART Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 356) Serena Spudich¹, N Lollo¹, B Chang², and R Price¹ ART that fails to completely suppress systemic HIV down-regulates local macrophage activation in the central nervous system, though not to the degree noted in those with complete viral suppression. This may be related to direct antiviral drug effect on central nervous system infection and consequent local activation within the central nervous system or to reduced systemic immune activation and viral traffic into the CSF and brain. The inhibition of intrathecal immune activation by ART, even in the absence of complete plasma HIV suppression, may contribute to preventing or ameliorating the neuropathogenic processes underlying ADC.
357	PREDICTIVE INDICATORS OF DISEASE PROGRESSION IN HAART-TREATED PATIENTS WITH HIV-RELATED LEUKOENCEPHALOPATHIES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 357) Serena Delbue¹, M Saresella¹, E Marchioni², F Guerini¹, I Marventano¹, G Spoladore³, G Sotgiu⁴, M Schifino², R Maserati³, and P Ferrante¹ CD4+ cells count, CSF HIV RNA levels, and Scripps Neurological Rating Scale scores significantly differ between NDLE and PML during the follow-up, being indicative of a better clinical outcome of NDLE than PML patients. Regarding PML, our findings suggest the brain as a possible site of latency for JCV and that in the classic form of PML, high CSF JCV viral load is predictive of poor survival.
358	STABILITY OF CNS DISEASE IN HIV-INFECTED CHILDREN DURING THE HAART ERA Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 358) P Wolters^1,2, S Martin^1,2, M Toledo-Tamula^1,2, S Zeichner², L Civitello^2,3, and Rohan Hazra² Despite treatment with HAART, a substantial number of children and adolescents with HIV infection exhibit evidence of CNS disease. Over a 2-year period in the HAART era, this CNS disease appears relatively stable. New strategies need to be developed to prevent or reverse this major complication of pediatric HIV infection.
Session 70—Poster Abstracts Neuropathogenesis: Therapy and Clinical Studies
359	NNRTI MORE THAN BOOSTED PI EXPOSURE ENHANCES VIROLOGICAL CONTROL IN CEREBROSPINAL FLUID OF HIV-1-INFECTED PATIENTS WITH NEUROLOGICAL DISORDERS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 359) Maria Letizia Giancola¹, P Lorenzini¹, A Cingolani², D Larussa¹, S Bossolasco³, M Bongiovanni⁴, L Monno⁵, A d'Arminio Monforte⁴, P Cinque³, A Antinori¹, and Italian Registry Investigative Neuro AIDS Study Group Exposure to NNRTI and, in lower measure, to boosted PI increases probability of CSF HIV-1 suppression during therapy. Including a higher number of neuroactive drugs in the HAART regimen results in a more effective control of CSF HIV-1 replication in neurologically impaired patients.
360	CEREBROSPINAL FLUID HIV INFECTION IN RELATION TO SYSTEMIC INFECTION AND TREATMENT IN DIFFERENT STAGES OF HIV DISEASE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 360) Gabriele Arendt¹, T Nolting¹, C Frisch¹, I W Husstedt², E Koutsilieri³, M Maschke⁴, A Angerer⁴, S Sopper⁵, P Riederer³, V Ter Meulen³, and the Competence Network HIV/AIDS The data provide 2 main messages. First, HIV-1/AIDS patients seem to have an individual “set-point” for CSF disease, which provokes an inflammatory process only incompletely influenced by ART; in treated late-stage patients there is no correlation of central nervous system deficits with CSF viral load. Second, a subgroup of patients exhibits a “primary” central nervous system disease manifestation. Factors contributing to the higher CSF than plasma viral load in some individuals must be clarified in further studies.
361	ACTG 736: CSF HIV-1 AND COGNITIVE FUNCTION IN INDIVIDUALS RECEIVING POTENT ANTIRETROVIRAL THERAPY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 361) C Marra¹, S Sinha², S Evans², S Letendre³, R Coombs¹, F Aweeka⁴, D Clifford⁵, S Shriver⁶, X Li⁷, Kevin Robertson⁸, and ACTG 736 Team In this cohort of subjects with advanced HIV infection, beginning or changing a potent ART regimen led to decline in CSF HIV RNA at week 24 and 52. In general, better virologic responses were seen in ART-naïve subjects. Greater decline in CSF HIV RNA was seen in subjects who took drug regimens that had better CNS penetration. Inclusion of CNS-penetrating ART may lead to better virologic control within the CNS.
362	NEUROCOGNITIVE IMPAIRMENT IN HIV-INFECTED SUBJECTS ON HAART: PREVALENCE AND ASSOCIATIONS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 362) Kevin Robertson¹, K Wu², T Parsons¹, R Ellis³, M Smurzynski², R Bosch², J Wu², J McArthur⁴, A Collier⁵, S Evans², and the ACTG 5001 Protocol Team and the ACTG In this large, HAART-treated cohort, the prevalence of neurocognitive impairment, based on a screening battery, was notable (43%) suggesting that neurocognitive impairment is still frequent even in the era of HAART. In addition, the incidence of neurocognitive impairment during follow-up was relatively frequent. Low CD4 nadir (<200) was associated with an increased risk for of neurocognitive impairment. However, concurrent CD4 and viral load were not significantly associated with neurocognitive impairment, a finding that is distinctly different from pre-HAART cohorts. Future studies should evaluate potential predictors or risk factors for incident impairment to help identify possible interventions to reduce the effect of neurocognitive impairment.
363	COGNITIVE FUNCTION AND ADHERENCE IN INDIVIDUALS RECEIVING ART: HOW YOU THINK CHANGES WHAT YOU DO Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 363) Kevin Robertson, T Parsons, S Chauhan, J Liner, W Robertson, A Braaten, and C Hall We found that neurocognitive dysfunction is related to later ability to adhere to medications. It is likely that those with cognitive dysfunction may have more difficulty with adherence, creating a vicious cycle of lack of adherence, increased viral load, further immunosuppression, and increased cognitive dysfunction and neurological disease. Patients suspected of having cognitive dysfunction represent a group with special treatment needs, and efforts to enhance adherence should be maximized.
364	A PHASE II, PLACEBO-CONTROLLED, DOUBLE-BLIND STUDY OF THE SELEGILINE TRANSDERMAL SYSTEM IN THE TREATMENT OF HIV-ASSOCIATED COGNITIVE IMPAIRMENT Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 364) Giovanni Schifitto¹, N Sacktor², J Zhang³, S Evans³, D Simpson⁴, L Millar⁵, E Miller⁶, E Smith⁷, M Goodhead⁸, D Clifford⁹, and the ACTG A5090 Team The preliminary analyses of this 24-week trial suggest that selegiline treatment was safe but not effective at improving cognitive function in subjects with HIV-associated cognitive impairment relative to placebo. Additional analyses are underway to assess the effect of selegiline on quality of life and functional performance.
365	MULTI-DRUG RESISTANCE-1 GENE AND INDINAVIR CONCENTRATION IN CEREBROSPINAL FLUID AND PLASMA FROM HIV-INFECTED INDIVIDUALS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 365) J Marquie-Beck¹, R Ellis¹, M Buzzell¹, Edmund Capparelli¹, S Rought¹, J Corbeil^1,2, D Holland¹, S De Almeida¹, S Letendre¹, and the HNRC Group The MDR-1 C3435T polymorphism was associated with higher IDV levels in plasma and CSF, and the latter was, in turn, associated with improved virologic suppression. Higher levels of IDV are associated with lower viral loads for plasma and CSF. In this sample, MDR genotype was not related to viral load however in a larger sample this relationship may be present. MDR-1 genotype may affect the neurotherapeutic potential of ART regimens.
366	NEUROCOGNITIVE IMPAIRMENT, SYMPTOMATIC PERIPHERAL NEUROPATHY, AND DEPRESSION IN HIV-INFECTED OUTPATIENTS WITHIN THE ASIA PACIFIC REGION: FINDINGS OF THE APNAC STUDY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 366) Edwina Wright^1,2,3, B Brew^4,5, L Lal^2,3, D Imran⁶, W Lun⁷, A Kamarulzaman⁸, M Lim², K Robertson⁹, J McArthur¹⁰, S Wesselingh^1,2,3, and the APNAC Study Protocol Team HIV-related mild-moderate and severe NCI, symptomatic PN, and depression are common in HIV-infected outpatients at sites in Indonesia, China, and Malaysia. These conditions are largely under-diagnosed and require further study.
367	PHASE II TRIAL OF PROSAPOSIN-DERIVED PEPTIDES FOR HIV-ASSOCIATED SENSORY NEUROPATHIES: FIRST USE OF ELECTRONIC DIARY TO RECORD HIV-ASSOCIATED NEUROPATHIC PAIN Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 367) Scott Evans¹, D Simpson², D Kitch¹, D Clifford³, C Rehrig⁴, M Alton⁴, B Huang⁴, and J McArthur² Although the 6-week treatment with PRO was safe and well tolerated, it was not effective at reducing HIV-associated neuropathic pain relative to placebo. The use of an electronic diary to record neuropathic pain is novel in HIV-SN.
368	LONG-TERM EXPOSURE TO DIDEOXYNUCLEOSIDE ANALOGUES IN THE TREATMENT OF HIV INFECTION DOES NOT RESULT IN WORSENING POLYNEUROPATHY SIGNS OR SYMPTOMS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 368) Ronald Ellis, S Letendre, J Lonergan, J Marquie-Beck, D Lazzaretto, C Hung, and the HIV Neurobehavioral Res Ctr Group These data suggest that among patients who tolerate an initial period of d-drug therapy without developing neuropathic signs or symptoms, the great majority can safely receive d-drugs for extended periods.
369	L-ACETYL CARNITINE PREVENTS ANTIRETROVIRAL TOXIC NEUROPATHY IN AN IN VITRO MODEL Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 369) L Lal¹, S Wesselingh^1,2,3, G Tachedjian¹, D Tyssen¹, K Smyth¹, J Glass⁴, and Catherine Cherry^1,2,3 These results confirm fetal rat dorsal root ganglia as a useful model of ATN, with toxicity seen only from those NRTI associated with ATN clinically. LAC prevents ddI and d4T toxicity in this in vitro model, suggesting that LAC may be an effective means of preventing ATN in patients exposed to these agents. Controlled trials will be needed to confirm the efficacy of LAC in a clinical setting, and to determine whether it has a role in the treatment of established ATN.
Session 71—Poster Abstracts Population-Based Detection Strategies for Acute HIV-1 Infection
370	DETECTION OF ACUTE HIV INFECTION IN PREGNANT WOMEN Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 370) K Patterson¹, Peter Leone¹, S Fiscus¹, J Kuruc¹, S McCoy², L Wolf², E Foust², D Williams², R Ashby², and C Pilcher¹ Standard antibody tests miss at least 4% of the pregnant women in North Carolina who are infected with HIV; testing algorithms including pooling/RNA significantly improve performance. Despite high viremia in the mother, ART initiated early in acute HIV infection can be effective in preventing transmission to infants. Strategies to reduce residual perinatal transmission of HIV in the United States must address the risk of maternal infection during pregnancy.
371	SEXUAL TRANSMISSION RISK AND RAPID PUBLIC HEALTH INTERVENTION IN ACUTE HIV INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 371) Christopher D Pilcher¹, E Foust², R Ashby², J Kuruc¹, T Nguyen¹, L Hightow¹, N Harrison¹, S McCoy¹, D Williams², and P Leone^1,2 Partner counseling and referral services can be highly effective in the setting of acute HIV infection, where it can be focused on individuals with extraordinary immediate risk of transmission (>5% per coital act) and large numbers of risky contacts. Partner counseling and referral services can identify source patients actively transmitting HIV for additional counseling in as many as half of cases; in North Carolina, most source patients are chronically infected.
372	IDENTIFICATION OF EARLY HIV-1 GROUP M AND O, ANTIGEN POSITIVE, ANTIBODY NEGATIVE INFECTIONS IN A NON-SUBTYPE B ENDEMIC REGION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 372) Ana Vallari¹, P Bodelle¹, V Holzmayer¹, L Zekeng², L Kaptue³, N Ndembi³, L Gurtler⁴, G Schochetman¹, S Devare¹, and C Brennan¹ The antigen-positive, antibody-negative specimens, confirmed by PCR, represent recently acquired HIV infections. The identification of an early infection by CRF02 is not unexpected since CRF02 accounts for at least 60% of HIV-1 infections in Cameroon. However, group O infections represent <5% of HIV-1 infections in Cameroon. Identification of an early group O infection shows that while rare, group O is being transmitted within the population. Due to the lack of commercially available seroconversion panels for HIV-1 non-subtype B infections, these specimens are valuable for evaluating the ability of fourth-generation antigen/antibody combination assays to detect early non-subtype B infections. These results also demonstrate that there are early HIV p24 antigen-positive infections that are not identified by assays that detect only anti-HIV antibodies.
373	POPULATION-BASED SURVEILLANCE OF RECENT INFECTIONS IN QUEBEC (1999-2005) Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 373) Bluma Brenner¹, M Roger², D Moisi¹, B Spira¹, H Charest³, J P Routy⁴, M Wainberg¹, and Quebec PHI Study Group Routine genotyping is important for screening HIV-1 transmission and the spread of non-B infections, as well as for drug-resistance testing. Acute/early infection accounted for at least half of all reported subtype B transmissions. Non-B subtype infections are being rapidly introduced into Quebec, and public health policies must address evolving trends in HIV-1 transmission.
374	COST EFFECTIVENESS OF SCREENING FOR ACUTE HIV INFECTION: THE NORTH CAROLINA STAT PROGRAM Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 374) Kit Simpson¹, A Biddle², P Leone³, L Wolf³, D Williams², J Kuruc², S McCoy², B Miller², L Hightow², and C Pilcher² Screening negative samples for acute HIV infection using a pooled RNA testing approach should be considered in all settings with at least a 0.55% positive HIV test rate where urgent notification and follow-up are possible.
Session 72—Poster Abstracts Molecular and Immunopathogenesis of Acute HIV Infection
375	DIFFERENTIAL EFFECT OF ACUTE HIV-1 INFECTION ON NK CELL FUNCTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 375) Angela Meier, G Alter, N Teigen, E Rosenberg, T Allen, and M Altfeld Taken together, these data demonstrate significant perturbations in the NK cell compartment as early as acute HIV-1 infection, with an impairment of the overall NK cell response to mitogenic stimulation early in acute infection, while the NK cell response to MHC-devoid target, which is increased initially, but wanes over time.
376	DYNAMIC INTERPLAY BETWEEN NK AND HIV-1-SPECIFIC CD8+ T CELL ACTIVITY DURING ACUTE HIV-1 INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 376) Galit Alter, N Teigen, E Kalife, A Meier, M Lichterfeld, E Rosenberg, and M Altfeld During acute HIV-1 infection, NK cell numbers and activity dominate at a time when the adaptive immune response is still developing, and then decline with the appearance of HIV-1-specific CD8+ T cell responses. These data reflect a dynamic interplay between the innate and adaptive immune response during acute HIV-1 infection.
377	IMMUNOLOGICAL CORRELATES ASSOCIATED WITH CONTROL OF VIRAL REPLICATION DURING PRIMARY HIV INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 377) Christoph Boesecke¹, I Stahmer², H Jessen¹, A Jessen¹, H J Stellbrink², and J Van Lunzen² The immunological control of viral replication apparently depends on the strength and breadth of initial HIV-specific CTL responses in primary HIV infection, which are potentially augmented by the early initiation of HAART. The evolution of CTL responses develops rapidly during seroconversion. Genetic determinants played a minor role in this analysis. The massive immune activation during primary HIV infection normalizes during HAART followed by structured therapy interruption. The potential beneficial effect of structured therapy interruption remains unproven.
378	TRANSIENT CCR5+ CD38+++ CD4+ EFFECTOR TH1 CELLS IN THE PRIMARY RESPONSE TO VACCINIA COINCIDE WITH CONTROL OF VIRUS AND IMMEDIATELY PRECEDE MEMORY CD4+ T CELLS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 378) John Zaunders¹, W Dyer², M L Munier^1,3, S Ip^1,3, J Liu², E Amyes⁴, W Rawlinson⁵, J Sullivan², D Cooper³, D Cooper¹, and A Kelleher^1,3 Vaccinia inoculation provides an informative model for primary CD4 responses. Initial control of vaccinia replication correlated with an early cell-mediated response at the inoculation site (including CCR5+CD38+++ CD4+ T cells, based on peripheral measures), rather than with the development of either memory cells or neutralizing antibody. In contrast to HIV-specific CD4+ T cells, the initial burst of vaccinia-specific CD4+ T cells included more CD127 (IL-7R)+, IL-2+, and CTLA-4 cells. By inference, positive signalling driving IL-2+ memory cell differentiation may be reduced during primary HIV-1 infection, in addition to any cytopathic effect of infection.
379	EMERGENCE OF A CD27+ CD45RA+ HIV-SPECIFIC CD8+ T-CELL POPULATION WITH CHARACTERISTICS OF STABLE MEMORY CELLS AFTER INITIATION OF HAART DURING ACUTE PRIMARY HIV INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 379) Camille Lécuroux¹, J M Doisne¹, I Girault¹, C Goujard¹, C Deveau², M Sinet¹, and A Venet¹ In patients treated in the acute phase of primary HIV infection, we observed the emergence of an HIV-specific CD27+CD45RA+ CD8+ T-cell subset. This subpopulation is quiescent, presents a high potential of survival, can expand, and acquires antiviral capacities. These results suggest that this HIV-specific CD8+ T subset may represent a stable memory cell pool with optimal functional capacities.
380	SIMULTANEOUS PHENOTYPIC EVALUATION OF 2 LYMPHOCYTIC ARMS OF INNATE IMMUNITY, γδ, AND NK CELLS DURING PRIMARY HIV-1 INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 380) A Vecchi, P Biswas, P Mantegani, C Tassan Din, G Travi, C Fortis, and Giuseppe Tambussi At the observed interval of time we were unable to recognize any clear association between trends of NK cells or γδ T lymphocytes and neither the different therapeutic choices nor the immunovirological (viremia, CD4 and CD8 counts) features of primary HIV patients.
381	COMPARATIVE STUDY OF CYTOKINE EXPRESSION DURING PRIMARY INFECTION IN SIV_mnd-1-INFECTED MANDRILLS AND MACAQUES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 381) Richard Onanga¹, S Souquière¹, M Makuwa¹, A Mouinga-Ondeme¹, P Roques², and M Kazanji¹ The results, therefore, showed that despite close viral kinetics in the 2 monkey species, the cytokine profiles suggest a different immune response delineating the non-pathogenic or pathogenic effect of the virus; and thus cytokine might be used as an index of the host response at an early stage of infection.
382	ASSOCIATION OF VIRAL LOAD, CO-RECEPTOR TROPISM, ENVELOPE-MEDIATED MEMBRANE FUSION, AND NEUTRALIZING ANTIBODY SENSITIVITY WITHIN HIV TRANSMISSION PAIRS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 382) Frederick Hecht¹, W Huang², T Wrin², B Schweighardt², P Hunt¹, J Barbour¹, R Atchison³, C Petropoulos², R Grant^1,3, and S Deeks¹ The strong correlation between viral load in source and in spread partners suggests that virus characteristics are a key determinant of HIV replication in early infection. Although only a minority of potential source partners had dual/mixed virus, there appeared to be a selective establishment of infection or very early overgrowth of R5 variant donor virus. Dual-tropic virus transmission was associated with rapid CD4 T cell depletion. Aside from CXCR4 co-receptor use, transmitted viruses were remarkably similar to the source virus in membrane fusion capacity, use of CCR5, and susceptibility to neutralizing antibodies, suggesting few transmission or early selective pressures in these characteristics.
383	PREVALENCE OF X4 VIRUSES IN RECENT HIV-1 SEROCONVERTERS: INFLUENCE OF THE ROUTE OF TRANSMISSION ON OUTCOME Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 383) Carmen De Mendoza¹, C Rodriguez², P Leiva³, F Garcia⁴, J Eiros⁵, A Corral¹, A Aguilera⁶, J Colomina⁷, J Del Romero², V Soriano¹, and on behalf of the Spanish Seroconverter Study Group A significant proportion (16.3%) of recent HIV-1 seroconverters harbor X4 viruses. HIV subtype and drug resistance mutations do not seem to influence co-receptor usage. However, individuals infected after sharing needles carry more often X4 viruses than persons sexually infected. Moreover, X4 viruses are associated with increases in plasma HIV RNA at 12 months, while subjects infected with R5 viruses show slightly declines in plasma viremia.
384	GENETIC CHANGES IN HIV-1 NEF AFTER SEXUAL TRANSMISSION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 384) Colleen Noviello¹, D Smith¹, T Russell¹, D Richman^1,2, S Little¹, and J Guatelli^1,2 The nef coding region is relatively conserved across HIV-infected individuals; however, changes were identified between source and recipient partners that may represent selection occurring at the time of sexual transmission. One such change from the nef consensus sequence was a mutation near sequence encoding immune evasion in a chronically infected source; yet this change was not transmitted to the recipient, suggesting that this mutation came at a cost to viral fitness during transmission. Phenotypic analysis of these alleles will answer the question of whether specific Nef functions are selected during transmission.
385	SELECTIVE DEPLETION OF HIGH AFFINITY HIV-1-SPECIFIC CD8+ T CELLS AFTER PRIMARY HIV-1 INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 385) Mathias Lichterfeld, X Yu, S Mui, A Trocha, M Johnston, E Rosenberg, B Walker, and M Altfeld These data suggest that the initial recruitment of high-avidity HIV-1-specific CD8+ T cell may control viremia during acute infection, while their selective elimination during the subsequent disease process contributes to the loss of immune control during chronic infection.
386	OVER-EXPRESSION OF INHIBITORY RECEPTOR CTLA-4 BY ANTIGEN-SPECIFIC CD4+ T CELLS DURING PRIMARY HIV-1 INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 386) John Zaunders¹, S Ip^1,2, M L Munier^1,2, D Kaufmann³, K Suzuki¹, C Brereton¹, N Seddiki¹, B Walker³, D Cooper², D Cooper¹, and A Kelleher^1,2 The level of HIV-1 DNA found in the activated CD38+++ subset of CD4+ T cells was similar to other CD4+ T cells, arguing against their preferential infection during primary HIV-1 infection. Neither preferential apoptosis of HIV-specific CD4+ T cells, nor any large change in T regulatory cells was observed. However, a large majority of HIV-specific CD4+ T cells expressed CTLA-4 when stimulated in vitro, suggesting that this potent negative regulator will preclude further differentiation of these cells.
387	THE IFN-γ +874T/T POLYMORPHISM IS ASSOCIATED WITH REDUCED RISK OF SEXUAL TRANSMISSION OF HIV-1 INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 387) Jacob Nattermann¹, G Ahlenstiel², M Vogel¹, M Schulz¹, H Nischalke¹, T Sauerbruch¹, J Rockstroh¹, U Spengler¹, and Kompetenznetz HIV/AIDS Our data show that HIV-1 infection is associated with an increased frequency of the IFN-γ high producer genotype +874A/A, whereas the IFN-γ seems to be protective against sexual transmission of HIV-1 infection. Although IFN-γ is a cytokine with strong antiviral properties, this finding might be explained by the fact that IFN-γ has also been shown to up-regulate CCR5 expression on monocytes. As this major co-receptor for HIV-1 is present in the mucosa, up-regulation of mucosally expressed CCR5 might increase susceptibility of these cells for HIV infection during sexual intercourse.
388	HIGH AUTOLOGOUS NEUTRALIZING ANTIBODY TITERS IN EARLY INFECTION WITH SUBTYPE C HIV-1 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 388) J Decker¹, F Bibollet-Ruche², X Wei¹, J Mulenga³, S Allen⁴, E Hunter⁴, B Hahn², G Shaw¹, J Blackwell⁴, and Cynthia Derdeyn⁴ These data demonstrate that subtype C Env elicit a potent neutralizing antibody response against newly transmitted Env with IC₅₀ titers that often exceed 1:2000. The high titers could be linked to the fact that newly transmitted subtype C Env tend to be more compact and less glycosylated than the subtype B Env. The lack of cross-neutralizing activity mediated by subtype C plasma against heterologous subtype C Env argues that neutralizing antibodies in these subjects do not recognize common epitopes as frequently as those found in subtype B infection, where low titers of cross-neutralizing activity were common. This study suggests the possibility of biological differences between early infection with subtypes B and C that are consistent with those observed during heterosexual clade C transmission, and these differences could be relevant to vaccine design.
Session 73—Poster Abstracts Acute HIV Infection: Natural History and Clinical Observations
389	TIME TO HIV-1 SEROCONVERSION IS SIMILAR AMONG PATIENTS WITH ACUTE HIV-1 INFECTION, BUT THERE ARE EXCEPTIONS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 389) Susan Morpeth¹, N Thielman¹, J Giner¹, P Menezes², S Fiscus², G Tomaras¹, C Pilcher², J Lennox³, J Eron², and C Hicks¹ Subjects diagnosed with acute HIV infection while ELISA-negative had a significantly higher viral load than those who had already seroconverted, but nadir CD4 counts did not differ. Median time to a reactive HIV-1 ELISA from onset of symptoms also did not differ perhaps because timing of ELISA testing was more dependent on non-biological factors such as clinician experience. One patient who rapidly progressed to AIDS did not seroconvert for a full year, despite evidence of functional B cell responses to non-HIV antigens. Virus targeting of HIV-1-specific T cells that augment specific B cell responses may explain this observation.
390	A COMPARISON OF METHODS FOR ESTIMATION OF DATE OF HIV INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 390) Tim Ramacciotti^1,2, P Grey¹, P Cunningham^2,3, J Jin¹, R Finlayson⁴, M Bloch⁵, R McFarlane⁶, J Kaldor¹, D Cooper^1,2,3, A Kelleher^1,2,3, and the PHAEDRA, AIEDRP, and Sydney Primary HIV Physicians Network Study Groups While the specific symptoms apparent during seroconversion may vary, the majority of patients report some typical symptoms. The use of symptom onset date to estimate the date of infection appears to increase accuracy and reduce variation, compared with the midpoint method. Together with laboratory evidence of primary HIV infection (p24 antigen-emia, negative Western blot, etc.), symptom onset date may provide a reliable estimate of time from infection, even in the absence of a previous negative EIA.
391	LONGITUDINAL ANALYSIS OF CLINICAL MARKERS FOLLOWING ART INITIATED DURING ACUTE OR EARLY HIV-1 INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 391) Sigall Kassutto^1,2, K Maghsoudi³, M Johnston², G Robbins², N Burgett², P Sax⁴, D Cohen⁵, V Degrutolla³, B Walker², and E Rosenberg² Early therapy of HIV-1 infection is well-tolerated and results in rapid and sustained virologic suppression. Preservation of CD4+ T lymphocyte counts may be achieved with early therapy independent of seroconversion status. PI-based and NNRTI-based regimens showed comparable performance in tolerability, time to virologic suppression, and CD4+ count when used as a first regimen for acute/early infection.
392	HSV-2 AND HIV-1 CO-INFECTION DOES NOT ALTER THE HIV-1 VIRAL SET-POINT AFTER EARLY HIV INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 392) Edward Cachay¹, S Frost¹, D Smith¹, D Richman^1,2, and S Little¹ In this large well-characterized cohort of recently HIV-infected men, HSV-2 seropositivity was common; however, HSV-2 seropositivity influenced neither baseline HIV viral loads nor HIV-1 viral set-point during early HIV infection.
393	THE RELATIONSHIP BETWEEN SYMPTOMS AND VIRAL LOAD IN THE ACUTE RETROVIRAL SYNDROME Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 393) Colleen Kelley, J Barbour, and F Hecht More symptoms experienced during acute retroviral illness predicted higher viral load. Our findings suggest that prior observations that more symptomatic acute infection is associated with more rapid disease progression reflect an association between symptoms and higher viral load in initial disease. However, initial viral load was a much stronger predictor of viral load set-point than symptoms, suggesting that clinicians should focus on early viral load rather than symptoms to predict subsequent disease course.
Session 74—Poster Abstracts Therapeutic Interventions in Acute HIV Infection
394	HIV-SPECIFIC IMMUNE RESPONSES FAIL TO PREDICT CD4 DECLINE OR CLINICAL OUTCOME FOLLOWING TREATMENT AT PRIMARY HIV-1 INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 394) Julie Fox¹, T Scriba¹, J Weber¹, R Philips², and S Fidler¹ SCART at primary HIV-1 infection is safe. It does, however, lead to variable long-term preservation of HIV-1-specific CD4 responses, the presence of which does not predict clinical outcome. A randomized control study is now underway.
395	INFLUENCE OF HIV-1 INFECTION STAGE AND ART ON THE DISTRIBUTION OF NK CELL SUBPOPULATIONS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 395) Claudio Fortis¹, K Titanji², A De Milito², L Lopalco³, P Mantegani¹, C Tassan Din¹, G Tambussi¹, and F Chiodi² Our results indicate that although the total numbers of NK cells are not significantly altered, imbalance in NK cell subsets may represent an intrinsic defect initiated by HIV early during infection to disarm the innate immune response to the virus. Though seemingly effective when administered during primary HIV infection, the effectiveness of ART in preventing NK cell subset imbalance in the long run is not clear, given the fact that chronic HIV patients, despite successful ART had an abnormal distribution of NK cell subsets. This indicates a link between disease progression and NK cell subset imbalance.
396	SEMEN HIV DYNAMICS AND EFFECT OF ART FOLLOWING PRIMARY HIV INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 396) Joanne Stekler¹, B Sycks¹, S Holte^1,2, J Maenza¹, C Stevens¹, J Dragavon¹, T Schacker³, A Collier¹, and R Coombs¹ The modest relationship between HIV levels in blood and seminal plasma and possibly differing patterns of viral decay in the 2 compartments suggest that infectiousness of primary infection may vary from estimates using blood levels. Incorporating seminal plasma HIV levels may strengthen models of transmission risk during primary infection. Our limited data from treated men are consistent with reduced genital tract drug penetration of PI compared with NNRTI, a topic deserving further study.
397	INCREASE OF THE HIV-1 NON-B SUBTYPES FREQUENCY AND RESPONSE TO HAART IN PATIENTS ENROLLED IN THE FRENCH PRIMO COHORT STUDY AND TREATED AT THE TIME OF PRIMARY INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 397) Marie-Laure Chaix¹, C Deveau², C Goujard³, J Galimand¹, N Saïchi², Z Nagy², I Pellegrin⁴, C Delaugerre¹, L Meyer², C Rouzioux¹, and the ANRS Primo Study Group We observed in France, an increase of the frequency of non-B strains in primary infected patients. Our results suggest that viral subtypes do not affect first-line HAART efficacy started early after primary infection, which is encouraging in view of the worldwide spread of non-B subtypes and of the increasing availability of ART in developing countries.
398	CLINICAL AND IMMUNOLOGICAL EFFECT OF HAART DURING ACUTE HIV INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 398) Hendrik Streeck¹, H Jessen², G Alter³, A Jessen², J Lunzen⁴, I Stahmer⁴, M Lichterfeld³, B Walker⁵, M Altfeld³, and J Rockstroh¹ Our data suggest that despite a boosting of immunological functions and T-cell maturation following 6 months of therapy in acute HIV-1 infection, this intervention had no effect on immunological control of HIV-1 replication.
399	CD8+ T CELL ACTIVATION IS LOWER DURING EARLY ART AMONG PATIENTS INFECTED WITH AN HIV-1 OF LOW POL REPLICATION CAPACITY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 399) Jason Barbour¹, M McGrath¹, R Grant^1,2, M Segal¹, J Weidler³, M Bates³, and F Hecht¹ The pol RC assay measures features of the HIV-1 lifecycle that are associated with persistent T-cell activation while on HAART, such as viral replication below the limit of quantification, or altered host tissue range. Persistent activation predicts lower CD4+ recovery and may mediate the relationship between pol RC and CD4+ recovery.
400	EFFECTS OF HAART DURING ACUTE HIV-1 INFECTION ON IMMUNE RESPONSES AND HIV-1 PROVIRAL DNA Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 400) Catherine Burton¹, C Mela¹, A Pires¹, M Nelson², B Gazzard², F Gotch¹, and N Imami¹ Anti-Tat CD8 responses waned within the course of the study, most likely due to early viral escape, while anti-Nef and anti-Gag responses became dominant, suggesting that even early HAART intervention might not be enough to prevent viral escape from immune control. The lower levels of HIV-1 proviral DNA in individuals commencing HAART during recent or acute HIV-1 infection demonstrates the association between early initiation of HAART and decay of the cellular HIV-1 reservoirs.
401	DYNAMICS OF T CELL IMMUNOPHENOTYPIC ALTERATIONS IN ART-TREATED AND UNTREATED PATIENTS WITH ACUTE AND EARLY HIV INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 401) Lena Al-Harthi¹, S Mawhinney², E Connick², R Schooley^2,3, J Forster², C Benson^2,3, M Thompson⁴, F Judson^2,5, F Palella⁶, and A Landay¹ Baseline activation of CD8-naïve and memory; and CD4 memory T cells, as indicated by Ki67 expression, is higher in acute treated than early treated subjects. Nevertheless, the immunophenotypic changes are not statistically different at week 48. This may suggest the extent of immunologic recovery as assessed by phenotypic markers is not negatively impacted by a delay of treatment beyond the acute stage of disease.
402	PRIMARY HIV-1 INFECTION: PLASMA DILUTION FOR PEAK VIREMIA LEVEL AND RESPONSE TO TREATMENT Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 402) Corinne Amiel, A Kara, V Schneider, M Lebrette, C Lependeven, G Pialoux, and J Nicolas Peak viremia during primary HIV-1 infection often exceeds 5 million copies/mL, and conventional HAART regimen is sufficiently powerful to decrease HIV replication rapidly and dramatically. Treating patients only during the first 6 months of HIV infection could preserve T lymphocyte repertoire and maintain good immune responses.
Session 75—Poster Abstracts Innate Immunity in HIV Infection
403	FEWER CIRCULATING PLASMOCYTOID DENDRITIC CELLS ARE PREDICTIVE OF VIROLOGIC AND IMMUNOLOGIC FAILURE IN HIV-SUPPRESSED PATIENTS, REGARDLESS OF CD4 COUNT Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 403) M Lichtner¹, R Rossi¹, F Mengoni¹, I Sauzullo¹, M Rizza¹, A Hosmalin², V Vullo¹, and Claudio Maria Mastroianni¹ The enumeration of pDC in peripheral whole blood by a single-platform method may represent a useful immunologic surrogate in the management of HIV disease. Our data suggest that the persistence of low circulating levels of pDC in ART-suppressed patients could be predictive of subsequent CD4 decline and virologic treatment failure.
404	CLASS A, B, AND C CpG-ODN DIRECTLY ACTIVATE PLASMACYTOID DENDRITIC AND B CELLS AND INDIRECTLY ACTIVATE NK AND iNKT CELLS IN HIV+ PATIENTS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 404) Jeffrey Martinson¹, A Tenorio¹, L Al-Harthi¹, C Gichinga¹, A Krieg², and A Landay¹ The ability of Class A, B, or C CpG-ODN to directly regulate the activation of pDC and B cells and indirectly activate NK and iNKT cells supports the utility of these adjuvants as therapeutic modulators of cellular components of the innate immune system in HIV infection.
405	TOLL-LIKE RECEPTOR-9 STIMULATION OR ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITY OVERCOMES THE BLOCK AGAINST NK LYSIS OF AUTOLOGOUS HIV-1-INFECTED CD4+ T CELLS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 405) Costin Tomescu, J Chehimi, L Azzoni, and L Montaner Our data suggest that HIV-1-infected autologous CD4 primary T cells can be lysed by NK cells in the presence of accessory cell factors or HIV-specific antibodies. These findings highlight the cooperative role that multiple cell types from both the innate (plasmacytoid DC) and adaptive (B cell) immune response play in mediating NK cytotoxic responses against HIV-infected targets. Therefore, our data are of particular relevance to prophylactic vaccine approaches where the generation of anti-HIV antibodies will be present within functional NK and accessory cell function.
406	VACCINE PROTECTION CORRELATES WITH MAINTENANCE OF INNATE IMMUNITY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 406) Steven Bosinger^1,2, A Danesh^2,3, D Persad², L Xu², L Ran², M Parenteau⁴, J Fournier⁴, E Rud⁴, and D Kelvin^2,3 These data suggest that type I ISG do not regulate attenuated vaccine-mediated protection to SIV, and that CXCL10 is an indicator of viremia. However, our data do suggest that protection is positively correlated with maintenance of TLR expression on peripheral blood leukocytes.
407	SWITCH IN C-TYPE LECTIN RECEPTOR PHENOTYPE FROM NKG2A TO NKG2C IN HIV-1 INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 407) Christopher Mela¹, C Burton¹, N Imami¹, M Nelson², M Bower², A Steel², B Gazzard², F Gotch¹, and M Goodier¹ We demonstrate a dramatic switch from NKG2A (inhibitory receptor) to functional NKG2C (activatory receptor) expressing NK cells in HIV-1-infected individuals with a redistribution of NCR and KIR expression in these subsets. This emergence of NKG2C+ NK cells may have consequences for the recognition and survival of infected CD4+ T cells in HIV-1+ individuals.
408	γ/δ T CELLS REMAIN FUNCTIONAL IN SIV+ MANGABEYS EXHIBITING AIDS DEFINING CD4 T-CELL LEVELS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 408) David Kosub¹, D Zhou¹, J Milush¹, G Silvestri², and D Sodora¹ γ/δ-T-cell cytokine production is maintained or increased during the dramatic decline in CD4 T cells observed in the SIV+ CD4-low mangabeys. Functional activity of γ/δ-T cells may be paramount in preventing the SIV+ CD4-low mangabeys from progressing to simian AIDS providing a potential target for novel immunotherapy in HIV+ patients.
409	PERCENTAGE AND FUNCTION OF NKT CELLS, POTENTIAL ANTI-HIV EFFECTOR CELLS, ARE PRESERVED BY BEGINNING HAART DURING ACUTE AND EARLY HIV-1 INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 409) Sandhya Vasan¹, M Poles^1,2, A Horowitz¹, E Siladji¹, M Markowitz¹, and M Tsuji^1,2 This study presents the first evidence that NKT cell function is impaired during early HIV infection, but significantly improves with effective treatment with ART. NKT cells are also shown to display anti-HIV-1 activity in vitro, mediated by IFN-γ secretion. Preservation of NKT cell function may therefore be important in HIV-infected individuals.
Session 76—Poster Abstracts HIV-1 Specific Humoral Immune Responses
410	PATTERNS OF CROSS-CLADE NEUTRALIZING ANTIBODY RESPONSES IN HIV-1-INFECTED CAMEROONIANS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 410) Y Blount¹, P Foujungo¹, M Kalou¹, P Raghunathan¹, G Alemnji¹, D Montefiori², M Callahan¹, S Butera¹, J Nkengasong¹, and Chunfu Yang¹ Our preliminary analysis indicates that in Cameroon, a country where multiple HIV-1 subtypes and recombinants circulate, the majority of persons with HIV-1 infection produce cross-clade neutralizing antibodies with some degree of reactivity against diverse primary HIV-1 strains. Thus, comprehensive analyses of cross-clade neutralizing antibody responses may provide valuable information on vaccine design and effective strategies in HIV prevention.
411	WHAT DETERMINES THE STRAIN SPECIFICITY OF THE NEUTRALIZING ANTIBODY RESPONSE? Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 411) Melissa Laird¹, T Igarashi², M Martin², and R Desrosiers¹ These neutralization studies demonstrated exquisite strain specificity to the neutralizing response that parallels the strain specificity seen during natural human infection with HIV-1. The SHIV-DH12 and SHIV-KB9 have distinct envelope glycoproteins, with the vast majority of amino acid sequence variation confined to discrete variable regions. To discern which loops may be contributing to this strain specificity, chimeric viruses have been designed in which the V1/V2 loops, V3 loop, or V4 loop are exchanged between SHIV-DH12 and SHIV-KB9 alone and in combination. Neutralization analyses of these chimeric viruses with KB9-postive sera and DH12-positive sera will clarify the role of the variable loops in the strain specificity of neutralization and may help identify the contribution of each loop to this strain specificity.
412	STRUCTURAL FEATURES OF THE V3 REGION OF HIV-1 ENV: 3 CLASSES OF ANTI-V3 ANTIBODY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 412) Milloni Patel, N Hoffman, and R Swanstrom These results suggest that the 3 classes of binding by anti-V3 antibodies to full-length Env and V3 peptides reflect 3 distinct structural elements of the V3 region. The data also imply that the structure of V3 differs between subtype B V3 and subtype C V3 in ways that could affect V3 immunogen design.
413	NOVEL HIV-1 NEUTRALIZING HUMAN ANTIBODIES RECOGNIZING CONSERVED CONFORMATIONAL EPITOPES ON gp41 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 413) Mei-Yun Zhang¹, V Choudhry¹, I Sidorov¹, B Vu¹, H Lu², D Montefiori³, G Quinnan⁴, S Jiang², C Broder⁴, and D Dimitrov¹ Our results suggest the existence of new conserved conformational neutralization epitopes on gp41 that may have potential as HIV vaccine immunogens and as targets for therapeutics.
414	V4 MUTATIONS AND NEUTRALIZATION ESCAPE IN SIV Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 414) Casmiar Nwaigwe, H Grieser, and K Cole Partial deletion of the V4 region likely resulted in abrogation of neutralizing monoclonal antibody binding by causing conformational changes in Env that resulted in disruption of the discontinuous antibody binding site. Furthermore, these results suggest the existence of potential interactions between the V1/V2 and V4 regions of Env in its trimeric form on the virus particle, and that these interactions may involve conformational epitopes important for recognition of neutralizing antibodies.
415	A ROLE OF MUTATIONS IN NON-V3 ENVELOPE REGIONS FOR ESCAPE FROM A BROAD NEUTRALIZING ANTI-V3 MONOCLONAL ANTIBODY, KD-247, DURING IN VITRO SELECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 415) Junji Shibata¹, K Yosihmura¹, A Honda¹, T Murakami², A Koito¹, and S Matsushita¹ In the present study, upon selection of HIV-1_MOKW in the presence of low concentration of KD-247, the escaped variants appeared with mutations in the V2 and C3 regions, but not in V3. These data suggest that HIV can escape from anti-V3 antibody by acquiring mutations in non-V3 region in an environment of low concentration of the antibody.
416	DETECTION OF ANTIBODIES TO MAJOR NEUTRALIZING EPITOPES OF THE HIV-1 ENVELOPE IN SERA FROM LONG-TERM NON-PROGRESSORS: PREVALENCE AND ASSOCIATION WITH BROADLY NEUTRALIZING ACTIVITY OF THESE SERA Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 416) M Braibant¹, S Brunet¹, D Costagliola², C Rouzioux³, H Agut⁴, B Autran⁴, and Francis Barin¹ Higher 2G12-like antibody levels are associated with broad neutralizing activity in LTNP sera, suggesting that the antigenicity of the “silent face” of gp120 should continue to be analyzed in depth to help find ways to induce broadly neutralizing antibodies.
417	MONOCLONAL ANTIBODIES DIRECTED AGAINST THE GB VIRUS C MAJOR ENVELOPE GLYCOPROTEIN NEUTRALIZE HIV INFECTIVITY DIFFERENTIALLY IN PBMC THAN IN TZB-bl CELLS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 417) Jinhua Xiang¹, J McLinden¹, Q Chang¹, D Klinzman¹, T Kaufman¹, D Montefiori², A Engel³, G Hess⁴, D Zdunek³, and J Stapleton¹ Monoclonal antibodies against GBV-C E2 protein against a conformational antigenic region contain broad, though weak, neutralizing activity against HIV in PBMC. Most of these antibodies do not appear to inhibit HIV in cell lines, although 1 (BD) appeared to have activity at concentrations <5 µg/mL in the TMZ-bl cell system. Determination of the structural features of this GBV-C E2 antigenic site may provide a novel immunogen for HIV vaccine development, and may explain the prolonged survival of prior GBV-C infection in HIV+ people observed in several clinical studies.
Session 77—Poster Abstracts Role of CD4+ T-Cell Response in Viral Control
418	CD4+ T CELL TARGETING OF HIV-1 PEPTIDE SEQUENCES PRESENT IN VIVO DURING CHRONIC, PROGRESSIVE HIV-1 DISEASE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 418) Eli Boritz, R Rapaport, T Campbell, J Koeppe, and C Wilson Many of the HIV-1-specific CD4+ T-cell responses we detected in vitro targeted amino acid sequences present in vivo, raising the question of how those cells avoided preferential infection and depletion by HIV-1 during chronic, progressive disease. Furthermore, the lack of in vitro p24-specific CD4+ T cell reactivity in subjects with viral loads >100,000 did not result solely from divergence of autologous epitope sequences and HXB.2, but may instead reflect an absence or loss of CD4+ T cells targeting the HIV-1 epitopes present in vivo.
419	HIV-1 IMMUNE EVASION OF CD4+ IMMUNE RESPONSES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 419) Moraima Pagan¹, J Heitman¹, D Hirschkorn¹, and P Norris^1,2 These results indicate that HIV can evade CD4+ T cell responses through modulation of HLA class II expression in infected CD4+ T cells. The model we have developed will allow the analysis of components of HIV that are responsible for HLA class II down-modulation and potential escape from immune control.
420	PERSISTENTLY HIGH FREQUENCIES OF HIV-SPECIFIC CD4 T-CELL RESPONSES IN PATIENTS WITH DISCORDANT CD4 VIRAL LOAD OUTCOMES: 4-YEAR FOLLOW-UP Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 420) Nicola Mackie¹, T Scriba², G Scullard¹, N Robinson², T Barber¹, R Phillips², and J Weber¹ Some patients can maintain CD4 counts for prolonged periods in the face of persistent detectable viremia. These patients continue to have high frequencies of total CD4+ T-cell responses.
421	IMPORTANCE OF CD4+ T CELLS IN THE MAINTENANCE OF SIV-SPECIFIC CD8+ T MEMORY CELLS AND THEIR ROLE IN PROTECTION FROM SIV_mac251 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 421) Monica Vaccari¹, W P Tsai¹, A Hryniewicz¹, J Nacsa¹, J M Heraud¹, K Reimann², D Panicali³, and G Franchini¹ All animals will be challenged shortly with SIV_mac251, and it is expected that the modulation of the vaccine-induced CD8+ T cell response will have a substantial effect on SIV_mac251 replication.
422	CD4 T-CELL MAINTENANCE IN TREATMENT-EXPERIENCED PATIENTS WITH VIRAL FAILURE: ASSOCIATION OF NADIR CD4 T-CELL COUNT, IMMUNE ACTIVATION, AND REPLICATION CAPACITY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 422) Miguel Goicoechea¹, C Spina^1,2, J Currier³, C Kemper⁴, M Witt⁵, J Leedom⁶, D Forthal⁷, J McCutchan¹, D Richman^1,2, R Haubrich¹, and California Collaborative Treatment Group Higher RC and greater levels of immune activation may predict CD4 decline in patients with ART failure.
423	COMPLETE CONTROL OF PLASMA HIV RNA LEVELS IN THE ABSENCE OF THERAPY IS ASSOCIATED WITH HIGH LEVELS OF LESS DIFFERENTIATED HIV-SPECIFIC CD4+ T CELLS AND LOW LEVELS OF T-CELL ACTIVATION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 43) Brinda Emu^1,2, E Sinclair^1,3, R Hoh², P Hsue², J Martin³, J McCune^1,3, and S Deeks² Complete suppression of HIV in the absence of therapy appears to be immunologically mediated and marked by high levels of HIV-specific IFN-γ+IL-2+CD4+ T cells. Immunophenotypically, these cells are enriched for a less differentiated phenotype (CD28+CCR7+CD27CD45RA) and exhibit low (but still abnormal) levels of T cell activation.
424	CORRELATION OF DIFFERENT T-CELL IMMUNE PARAMETERS IN HIV-INFECTED PATIENTS FAILING TO RECOVER CD4 T-CELL COUNT FOLLOWING LONG-TERM HAART Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 424) Giulia Marchetti¹, L Meroni¹, A Casabianca², M Magnani², M Clerici¹, D Trabattoni¹, C F Perno³, A d'Arminio Monforte⁴, M Galli¹, and A Gori⁴ The lack of CD4+ rescue in INR seems to reflect a highly activated apoptotic T-cell compartment, despite a substantial IL-7-mediated thymic replenishment. Intracellular HIV-DNA content could be strictly associated to deficiency of T-cell reconstitution. Whether these differences in T-cell immune reconstitution pattern and functional HIV-specific parameters will eventually result in accelerated disease progression, development of opportunistic infections, or immune deficiency-associated clinical conditions still remain to be assessed and will help define the possible value of immunological measurement in terms of clinical prognosis.
425	HETEROGENEITY IN THE RECOVERY OF POLYFUNCTIONAL HIV-1-SPECIFIC CD8 BUT NOT CD4 T-CELL RESPONSES FOLLOWING ART Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 425) Alexandre Harari, C Cellerai, G Tapia, D Ciuffreda, P A Bart, and G Pantaleo In contrast to HIV-1-specific CD4 T-cell responses, polyfunctional CD8 T-cell responses are not homogeneously recovered after ART. The recovery of polyfunctional HIV-1-specific CD8 T-cell response was also associated with a more rapid control of virus replication and a greater increase in CD4 T cells. Therefore, polyfunctional CD8, rather than CD4, T-cell responses are better immune correlates of protective antiviral immunity.
426	INNATE AND ADAPTIVE CORRELATES TO VIRAL SET-POINT BEFORE AND DURING TREATMENT INTERRUPTIONS IN CHRONICALLY SUPPRESSED HIV-1-INFECTED SUBJECTS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 426) Emmanouil Papasavvas¹, B Thiel¹, A Foulkes², V Maino³, A Hancock¹, M Lahti², J Kostman^4,5, K Mounzer⁴, J Shull⁴, and L Montaner¹ Plasmacytoid dendritic cells and the proliferative activity of anti-HIV IFN-γ-secreting CD4 T cells correlate inversely with viral set-point when measured before therapy interruption and may provide information on viral set-point when measured under ART.
427	ACQUISITION OF DIRECT ANTIVIRAL EFFECTOR FUNCTIONS BY CMV-SPECIFIC CD4+ T LYMPHOCYTES WITH CELLULAR MATURATION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 427) Joe Casazza¹, M Betts², D Price¹, M Precopio¹, J Brenchley¹, M Roederer¹, D Douek¹, and R Koup¹ Mature CMV-specific cells exhibit distinct functional properties similar to those observed in CD8+ T cells, including cytolytic activity and MIP-1β production.
Session 78—Poster Abstracts Role of CD8+ CTL Response in Control of HIV Infection
428	THE CONSERVED HLA B13- RESTRICTED CTL EPITOPE RQDILDLWI IN NEF IS AN IMMUNODOMINANT CTL EPITOPE IN HLA B13S HIV-1-INFECTED PATIENTS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 428) Thomas Harrer, M Bäuerle, S Bergmann, K Eismann, M Rittmaier, S Müller, A Goldwich, B Spriewald, and E Harrer We assume that the strong CTL reaction against this conserved CTL epitope in Nef could be an important factor for the published association of HLA B13 with a more favorable course of HIV-1 infection.
429	ESCAPE FROM AN IMMUNODOMINANT EPITOPE IN HLA-B27-POSITIVE INDIVIDUALS PREDICTS VIRAL LOAD OUTCOME Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 429) Palanee Ammaranond^1,2, K Petoumenos¹, M Middleton¹, N Doong³, R Finlayson⁴, M McMurchie⁵, D Van Bockel^1,2, D Cooper^1,2, J Kaldor¹, A Kelleher^1,2, and on behalf of the Australian LTNP Study Group The presence of the escape mutant and lack of the SDF1-3’A mutation were found to be independently related to higher viral load at the last visit. Escape is a major determinant of viral load in HLA-B27+ individuals.
430	SINGLE TCR-MEDIATED CROSS-RECOGNITION OF AN HIV-1 CYTOTOXIC T-CELL EPITOPE PRESENTED BY HLA-A3 AND HLA-A11 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 430) Xu Yu, M Lichterfeld, K Williams, S Mui, S Shah, A Kim, M Johnston, E Rosenberg, B Walker, and M Altfeld These data show that despite distinct TCR recognition of HLA-A3- or HLA-A11-presented HIV-1 peptides in the vast majority of cases, specific TCR can cross-recognize their cognate antigen in the context of both HLA-A3 and HLA-A11. Crystallization studies of these cross-reactive TCR might allow for the identification of structural features enabling promiscuous antigen recognition.
431	EX VIVO EVOLUTION OF HIV-1 CTL EPITOPE SEQUENCES IN CHRONICALLY INFECTED INDIVIDUALS REVEALS PARTIAL ESCAPE IN VIVO Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 431) Martha Lewis, M Dagarag, B Khan, and O Yang These results imply that CTL in chronic infection still exact a fitness cost even in the absence of complete escape, as evidenced by rapid sequence evolution after CTL pressure is removed. Thus, it appears that escape from the selective pressure exerted by CTL is not necessarily an all-or nothing phenomenon, but rather partial escape continues to impose a fitness cost that could contribute to their antiviral immune effects in chronic infection.
432	HIV-2 GAG-SPECIFIC RESPONSES ARE IMPORTANT IN CONTROL OF HIV-1 VIRAL LOAD IN DUALLY HIV-1- AND HIV-2-INFECTED INDIVIDUALS IN SENEGAL Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 432) Natalie Zheng¹, P Sow², S Hawes¹, H Diallo-Agne², A Robinson³, J Stern¹, Y Huang³, M McElrath^1,3, and N Kiviat¹ Among dually infected individuals, HIV-2 Gag-specific CD8 cell responses are associated with control HIV-1 replication and maintenance of HIV-1-specific CD4 help.
433	IDENTIFICATION OF A BROADLY RECOGNIZED, HIGHLY CONSERVED GAG CD4 T-CELL EPITOPE IN CONTROLLED HIV-1 CLADE C VIRUS INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 433) Danni Ramduth¹, C Day², C Thobakgale¹, P Kiepiela¹, P Goulder², B Walker³, and the HIV Pathogenesis Prgm Study Group Comprehensive analysis of HIV-specific CD4 T-cell responses in controlled clade C virus infection reveals uniform detection of Gag-specific IFN-γ responses, including targeting of a peptide in the Gag major homology region in the majority of persons tested. This region is analogous to the major B clade CD4 epitope, but cross-recognition occurred infrequently. IL2+ IFN-γ CD4 cells most frequently target the Gag protein, while other proteins, albeit containing CD4 T-cell epitopes, rarely elicit IL-2 responses.
434	THE SINGLE HLA-B57-KF11 SPECIFICITY IS ASSOCIATED WITH A 5- TO 10-FOLD REDUCTION IN VIRAL LOAD Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 434) Senica Chetty¹, A Leslie², P Kiepiela¹, B Walker¹, P Goulder^1,2, and HPP Study Group KF11 recognition differs significantly between HLA-B57 subtypes. B5703 responders to KF11 have a lower viral load than non-responders and B5702 subjects.
435	ASSOCIATIONS BETWEEN MHC CLASS I GENETIC DIVERSITY AND CLINICAL CORRELATES OF HIV DISEASE STATUS IN UNTREATED INFECTION: SUPPORT FOR A DOMINANT ROLE OF HLA-B Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 435) Zabrina Brumme^1,2, C Brumme¹, C Chui¹, C Woods¹, B Wynhoven¹, R Hogg^1,2, J Montaner^1,2, and R Harrigan^1,2 Results support frequency-dependent effects of MHC class I genes on HIV pVL, and confirm and extend reported associations between specific alleles (particularly at the HLA-B locus) and viral load set-point.
436	ENHANCED ANTIGENICITY OF HIV-DERIVED CD8+ T-CELL EPITOPES PRESENTED BY MAJOR HISTOCOMPATIBILITY COMPLEX CLASS I PROTEINS WITH INCREASED CO-RECEPTOR BINDING PROPERTIES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 436) David Price¹, L Wooldridge², E Gostick², A Oxenius³, J Brenchley¹, M Glick⁴, J Boulter⁵, H Van Den Berg⁶, D Douek1, and A Sewell² These data indicate a novel approach to the enhancement of antigen-specific cellular immunity that is testable in translational vaccination studies.
437	PRESERVATION OF T-CELL PROLIFERATION RESTRICTED BY PROTECTIVE HLA ALLELES IS CRITICAL FOR IMMUNE CONTROL OF HIV-1 INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 437) Helen Horton^1,2, I Frank¹, R Baydo¹, J Penn¹, D Lee¹, S Derosa^1,2, and M McElrath^1,2 Our findings suggest that the capacity to maintain CD8+ T-cell proliferation is dependent on the epitope and MHC restriction of the specific T cells. We show that most HIV-specific T cells lose proliferative capacity during chronic infection but that, within the same individual, T cells restricted by MHC alleles associated with non-progression (B27 and B57) maintain their proliferative capacity, permitting expansion and antiviral effector activities. Maintenance of proliferative capacity, regardless of MHC restriction, may serve as an important correlate of disease protection in the event of infection following vaccination.
438	CLONOTYPIC ANALYSIS OF THE TCRBV REPERTOIRE FROM FORMALDEHYDE-FIXED PBMC: MOLECULAR CHARACTERIZATION OF VIRUS-SPECIFIC CD8+ T CELLS IN THE ABSENCE OF A CONTAINED CELL SORTER Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 438) David Van Bockel¹, K Suzuki¹, K Warton², P Ammaranond¹, D Douek³, N La Gruta⁴, K Stanley², S Turner⁴, D Cooper⁵, and A Kelleher⁵ This novel method demonstrates detection of stable clonal preference in antigen specific CD8+ T-cells specific for CMV antigen in a longitudinal model of controlled infection. This technique will be used in HLA-B27+ LTNP to determine the role of TCR repertoire diversity of T cells, responding to an immunodominant epitope of HIV-1 (p24 Gag), in maintaining viral control.
439	ESTIMATING THE EFFECTIVENESS OF SIV-SPECIFIC CD8+ T CELLS FROM THE DYNAMICS OF VIRAL IMMUNE ESCAPE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 439) Judith Mandl¹, R Regoes², D Garber¹, and M Feinberg^1,3 Here we provide the first quantitative estimates of the in vivo effectiveness of specific CD8+ T cells. These data suggest that at least during acute infection, CD8+ T cells can have a significant effect on shortening the longevity of CD4+ T cells and appear to exert a pressure on the virus population that approximates (or may even exceed) that of HAART.
440	FACTORS AFFECTING THE IMPACT OF NEF-MEDIATED MHC I-DOWN-MODULATION ON HIV-1-SPECIFIC CTL ANTIVIRAL ACTIVITY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 440) S Adnan¹, A Balamurugan¹, A Trocha², M Bennett¹, H Ng¹, C Brander², and Otto O. Yang¹ These findings illustrate CTL targeting factors affecting the immuno-modulatory activity of Nef. CTL recognizing early protein epitopes remain susceptible to Nef-mediated MHC-I down-modulation, whereas C-restricted CTL are unaffected. MHC-I restriction by C alleles thus is a successful avenue to avoid immune evasion due to Nef, raising the questions of whether such responses should be a focus of immunotherapies and vaccines.
441	RELATIONSHIP BETWEEN PERFORIN EXPRESSION AND DEGRANULATION ACTIVITY IN VIRUS-SPECIFIC CD8 T CELLS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 441) Alexandre Harari, C Cellerai, D Ciuffreda, P A Bart, and G Pantaleo These data indicate that perforin and CD107a mobilization represent independent markers of CD8 T cells with potential cytotoxic capacity. In addition, perforin expression, but not CD107a mobilization, correlated with the stage of differentiation of memory CD8 T cells.
442	THE IFN-γ-PRODUCING CD8+CD45RA-CCR7-CD27+ T CELLS SPECIFIC FOR HIV-1 GAG BUT NOT FOR NEF DEFINE IMMUNE CORRELATES OF PROTECTION IN LTNP Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 442) Wei Lu¹, A Schnuriger¹, D Costagliola², C Blanc¹, B Da Silva¹, M Almeida¹, C Rouzioux³, B Autran¹, and the French ALT Study Group Gag-specific, but not Nef-specific, IFN-γ-producing CD8 T cells correlate with numbers of HIV-infected cells. This difference is related to a less differentiated status of CD8+CD45RACCR7CD27+ Gag-specific cells, which depends on preserved CD4 counts and might participate in the immune control of HIV.
Session 79—Poster Abstracts Critical Factors in Immune Reconstitution
443	GENE-GENE INTERACTIONS AND IMMUNE RECONSTITUTION DURING ART: ANALYSIS NWCS 233 OF ACTG PROTOCOL A5001 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 443) David W Haas¹, A Motsinger¹, D Geraghty², M Ritchie¹, R D'Aquila¹, D Unutmaz¹, C Benson³, and A Landay⁴ Multilocus interactions involving genes important for T-cell expansion and survival may predict CD4 increases during ART. Further studies are warranted to validate these associations and define underlying mechanisms.
444	OLDER PERSONS HAVE IMPAIRED RESTORATION OF NAÏVE CD4 CELLS, BUT GREATER INCREASES IN B CELLS IN RESPONSE TO HAART Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 444) Robert Kalayjian^1,2, R Matining³, P Tebas⁴, A Wu⁵, J Spritzler³, A Landay⁶, R Pollard⁷, M Ledermna², and Adult AIDS Clin Trials 5015 Study Team Older persons had impaired restoration of naïve CD4 cells, but greater increases in B cells with HAART. HAART-associated B-cell restoration is not well characterized and warrants further study. Naïve CD8 cell counts during HAART were higher than controls in both age groups, possibly implying different mechanisms of restoration between naïve CD4 and CD8 cells.
445	THE EFFECT OF RAPIDLY CHANGING HIV-1 VIRAL LOAD ON T-CELL SUBSETS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 445) John Murray¹, J Zaunders², M L Munier¹, P Grey¹, A Kelleher¹, M Bloch³, R Finlayson⁴, A Carr¹, J Kaldor¹, and D Cooper¹ Although many T-cell phenotypes were significantly correlated with VL (number or percentage of CD4 (CD8): 5 (11) positively and 10 (10) negatively) only some of these exhibited lasting effects. In the setting of acute infection and subsequent treatment, most T-cell alterations will be reversible but there will be a sustained increase in the terminally differentiated CD45RA+CD62L subsets of CD4+ and CD8+ T cells.
446	INTERFERON-ALPHA RESCUES T CELLS FROM SPONTANEOUS APOPTOSIS IN HIV DISEASE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 446) B Rodriguez, M Lederman, D Bazdar, and Scott Sieg IFN-α may have beneficial effects in HIV disease by rescuing T cells from apoptosis. Moreover, inhibition of apoptosis by IFN-α may enhance survival of CD8+ T cells more efficiently than CD4+ T cells in HIV disease.
447	FAILURE OF CO-STIMULATORY PATHWAYS AND NAÏVE CD4+ T-CELL EXPANSION IN HIV DISEASE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 447) Angel Luciano^1,2, S Sieg¹, D Bazdar¹, and M Lederman¹ Naïve CD4+ T cells in HIV+ persons fail to up-regulate co-receptors for T cell activation CD28 and CD27 after TCR stimulation. Failure of co-stimulatory pathways likely contributes to the naïve T cell expansion failure that characterizes HIV infection and may determine both failure of naïve T cell homeostasis in HIV infection and impaired generation of memory/effector CD4 T cells after antigen recognition.
448	CD127 EXPRESSION ON THYMIC SUBSETS IS DIFFERENTIALLY DOWN-REGULATED FOLLOWING IN VITRO HIV INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 448) Charlene Young and J Angel HIV infection in vitro alters CD127 expression on thymocytes suggesting that HIV may play a role in impaired thymic function by altering the IL-7 responsiveness of thymocytes. It appears that the various thymocyte subsets are differentially affected by HIV infection. Moreover, viral strains with different tropism appear to have distinct effects on CD127 expression as has been shown with other aspects of thymic function. These results may provide some insight into how HIV infection results in impair thymic function.
449	DIFFERENTIAL ROLE OF IL-7/IL-7R SYSTEM IN REGULATING T-CELL HOMEOSTASIS IN HIV-INFECTED PATIENTS AT DIFFERENT STAGES OF DISEASE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 449) Giulia Marchetti, M Cesari, L Meroni, F Franzetti, A Bandera, M Clerici, A d'Arminio Monforte, M Moroni, M Galli, and A Gori The observation that IL-7/IL-7R system is differentially modulated in HIV infection correlating with specific T-cell homeostatic pathways, suggests an accurately regulated system with a diverse regulatory function according to disease progression. Thus, the most appropriate and timely strategies exploiting IL-7 immunotherapy in HIV necessarily has to be modelled on disease stage and homeostatic parameters.
450	IMPAIRED IL-12-INDUCED RESPONSES IN HIV-1-INFECTED INDIVIDUALS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 450) Vainav Patel¹, A Valentin¹, R Yarchoan², and G Pavlakis¹ Our results demonstrate the existence of qualitative IL-12-specific defects in HIV-1 infection that are not restored upon exogenous supplementation. Correlation of impaired IFN-γ production with failure to expand CD4 T cells suggests a possible T-helper defect. Our data with HIV-1 peptides show that antigen-specific IFN-γ production is not driven by endogenous IL-12, and that IL-12-induced IFN-γ production is not predictive of specific responses to antigens. These data have implications for IL-12 immunotherapy in HIV-1 infection and may explain why recently concluded trials with this cytokine alone failed to boost HIV-1-specific immunity.
451	TRAIL EXPRESSION IN LYMPH NODE CELLS CORRELATES WITH CD4 RECOVERY IN PATIENTS ON HAART Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 451) Alain Lafeuillade, G Hittinger, A Cheret, and C Poggi This study shows different expression of pro- and anti-apoptotic factors between PBMC and LNMC in patients on HAART. Increased expression of TRAIL mRNA in lymph nodes was associated with poorer CD4 recovery despite undetectable viremia.
452	RESTORATION OF ANTI-TETANUS TOXOID RESPONSES IN PATIENTS INITIATING HAART: DIFFERENCES IN KINETICS IN THE PRESENCE OR ABSENCE OF BOOST IMMUNIZATION; AN INITIO IMMUNOLOGY SUB-STUDY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 452) Catherine Burton¹, R Goodall², A Samri³, B Autran³, A Kelleher⁴, G Poli⁵, G Pantaleo⁶, M Seligmann⁷, F Gotch¹, and N Imami¹ It may be unnecessary to routinely boost-immunize for tetanus toxoid, unless a clinical event dictates it, because anti-tetanus responses appear to eventually reconstitute when patients are successfully treated with HAART, irrespective of ART regimen.
453	RAPID QUALITATIVE AND QUANTITATIVE ANALYSIS OF T-CELL RESPONSES IN HIV-1-INFECTED INDIVIDUALS RECEIVING SUCCESSFUL HAART AND IN HIV-1 SERO-NEGATIVE CONTROLS: CONCOMITANT ASSESSMENT OF PERFORIN, IFN-GAMMA AND IL-4 SECRETION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 453) Catherine Burton, F Gotch, and N Imami We demonstrate the viability of ELIspot to measure perforin production. Evaluation of immunological response using the 3 ELIspot assays in combination reveals that the complexity of the T-cell response is greater than that suggested when quantitating the prototypical effector cytokine IFN-γ alone.
Session 80—Poster Abstracts Miscellaneous Immunological Observations
454	LEPROSY EFFECTS ON IMMUNE CELLULAR PARAMETERS OF HIV-1-INFECTED SUBJECTS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 454) Karina Salmazi¹, S Maeda¹, L Marti², J Yamashita¹, P Haslett³, and E Kallas¹ Increased T cell activation, shift to late stage differentiated CD4+ T cells, inversion of Vδ1:Vδ2 ratio and loss of peripheral blood plasmacytoid DC observed in co-infected subjects together suggest that active infection with M. leprae may further exacerbate HIV-1 disease pathogenesis. This is in contrast to the apparently protective effect of this mycobacterial co-infection on simian immunodeficiency virus (SIV) disease pathogenesis in rhesus macaques. Further studies are necessary to characterize functional immune interactions between these important pathogens.
455	GENE EXPRESSION IN CIRCULATING MONOCYTES IN HIV-1 INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 455) Malavika Srinivasan-Giri¹, M Nebozhyn¹, A Raymond¹, K Mounzer², C Nichols¹, C Gallo², J Ondercin², E Schmidt², L Showe¹, and L Montaner¹ Circulating monocyte subsets in HIV-1 infection bear an activated gene expression pattern supporting a constitutive state of cellular activation. This in addition is associated with an anti-apoptotic state of relevance to monocyte retention, disease progression, and macrophage viral reservoirs.
456	CYTOSKELETAL REMODELING OF THE HIV-INFECTED MACROPHAGE: PROTEOMICS AND FUNCTIONAL IMMUNOCHEMICAL ANALYSIS OF GIANT CELL FORMATION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 456) Irena Kadiu, P Ciborowski, M Ricardo-Dukelow, and H Gendelman The macrophage cytoskeleton is remodeled as a result of progressive viral infection and appears to act as a cytoplasmic effector of the virus, the host cell, and its ultimate fate.
457	THE CCL28/CCR3/CCR10 CIRCUIT IS UP-REGULATED IN HIV-EXPOSED BUT UNINFECTED INDIVIDUALS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 457) Manuela Borelli¹, S Lo Caputo², A Hernis¹, F Vichi², F Fasano¹, D Trabattoni¹, F Mazzotta², and M Clerici¹ The CXCL12 and the CCL28 systems, but not the CCL25 circuit, are up-regulated in EU. CXCL12 favors the recruitment of plasma cells and CCL28 attracts IgA ASC in the mucosal lamina propria; in particular it has been shown recently that CCR10 is specifically expressed by IgA-secreting cells. These results could therefore explain the IgA expression that characterizes the HIV-exposed but uninfected condition.
458	PAIRED PERIPHERAL BLOOD AND CERVICOVAGINAL SECRETION CHEMOKINE LEVELS IN EXPOSED UNINFECTED WOMEN: ELEVATED LEVELS OF BETA BUT NOT ALPHA CHEMOKINES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 458) Ajay Wanchu, R Sachdeva, P Suresh, and R Bagga Elevated levels of MIP-1α and MIP-1β in the peripheral blood and cervicovaginal secretions of EU may have a role in protecting these individuals from getting infected. This could have implications in vaccine development against HIV infection. The discordance between the peripheral blood and genital secretions might be accounted for by the 2 being separate immunological compartments.
459	DECREASED IL-7Rα (CD127) AND INCREASED CYTOKINE γ-CHAIN (CD132) EXPRESSION CORRELATES WITH ELEVATED PLASMA IL-7 LEVELS IN HIV INFECTION, AND PRECEDES LOSS OF VIRAL CONTROL Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 459) Sarah Sasson¹, J Zaunders², G Zanetti¹, E King¹, K Merlin², D Smith¹, K Stanley², D Cooper^1,2, and A Kelleher^1,2 Dysregulation of the IL-7/IL-7R system occurs early in HIV infection with marked reductions in the proportions of CD4 T-cells expressing CD127. The extent of this down regulation is associated with loss of viral control in LTNP. The mechanism of this depletion is the subject of ongoing investigation.
460	GRANULOCYTES ARE THE MAJOR PRODUCERS OF α-DEFENSINS 1, 2, AND 3 IN LYMPH NODES OF HIV-1 SEROPOSITIVE AND SERONEGATIVE INDIVIDUALS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 460) Joy Folkvord, M McCarter, J Ryder, R Schlichtemeier, and E Connick α-Defensins are up-regulated in reactive lymph nodes, including those in HIV-1 infection, and are expressed primarily by granulocytes. The role of this innate immune response in controlling HIV-1 replication in vivo merits further investigation.
461	STIMULATION WITH MYELIN BASIC OVERLAPPING PEPTIDES INDUCES APOPTOSIS AND SPECIFIC IMMUNE RESPONSE IN HIV POSITIVE PATIENTS WITH LEUKOENCEPHALOPATHIES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 461) Marina Saresella¹, S Delbue¹, E Colombo¹, I Marventano¹, S Minora¹, M Zanzottera¹, F Guerini¹, E Marchioni², and P Ferrante¹ The obtained data evidenced specific activation of immune system against self-antigen, such as MBP in patients with leukoencephalopathies and MS, together with a decrease of CD8+ apoptotic MBP-specific T cells in the same patients. On the whole, it could be suggested that the auto-reactive immune phenomena could play a role in PML, NDLE, and MS.
462	EPIGALLOCATECHIN GALLATE, GREEN TEA CATECHIN, BINDS TO T-CELL RECEPTOR, CD4, AND INHIBITS HIV-1-GP120: THERAPEUTIC POTENTIAL Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 462) Christina Nance^1,2, M Williamson³, S Paulson², T McCormick^1,2, and W Shearer^1,2 We have demonstrated clear evidence of high affinity binding of EGCG to the CD4 molecule. EGCG at concentrations equivalent to those obtainable by the consumption of green tea significantly reduces the attachment of gp120 to CD4. The competitive binding properties of EGCG for the CD4 binding sites by gp120 may translate to an HIV-1 preventative strategy. EGCG may have a potential use as adjunctive therapy in HIV infection.
463	IN VIVO MEASURES OF T-CELL RESPONSIVENESS ARE IMPAIRED EVEN IN EARLY HIV-1 INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 463) Christoph Lange¹, L Radler², G McComsey³, T Dreyer¹, M Lederman³, and J Andersson² In vivo measures of adaptive cellular immune responses are impaired even in early HIV infection and are not well reflected by numbers of circulating CD4+ T cells.
464	ASSOCIATION OF THE INSERTION OF CTTTT IN 5’UTR OF CD28 GENE WITH LOW LEVEL OF CD28 EXPRESSION IN T CELLS: INFLUENCE ON SUSCEPTIBILITY TO HIV-1 INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 464) Alex Soriano¹, H Oliva¹, F García¹, J Del Romero², C Rodríguez², A Barrasa², J Lorenzo³, M Plana¹, J Gatell¹, and T Gallart¹ Our results suggest that the insertion of CTTTT in 5’UTR of CD28 gene is associated with a low level of CD28 expression in T cells. This could contribute to the increased susceptibility to HIV-1 infection.
465	INCREASED CD25+/CD4+ TREG CELLS IN LYMPHOID TISSUE OF HIV+ PATIENTS TREATED WITH HAART AND STRUCTURED THERAPY INTERRUPTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 465) A Mozos, M Garrido, L Alós, M Plana, C Gil, T Pumarola, E Campo, A Martínez, J Gatell, and Felipe García The number of CD4+CD25+ Treg cells in lymphoid tissue of HIV-infected patients significantly improves after HAART and structured therapy interruption, and this recovery correlates with a decrease of the lymphoid tissue viral load and recovery of immuno-architecture. These results suggest that CD25+ Treg may play a role in the control of viral load and may be a useful index of immunological recovery on lymphoid tissue biopsies from HIV patients.
Session 81—Poster Abstracts HIV Vaccines: Preclinical Studies
466	ABSENCE OF INFECTION IN GUT AND LYMPH NODE TISSUES IN RHESUS MONKEYS AFTER REPEAT-DOSE MUCOSAL CHALLENGES FOLLOWING HIV-1 DNA/MVA IMMUNIZATIONS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 466) M Aidoo¹, R Otten¹, V Rodriguez², C Sariol², M Martinez², E Kraiselburd², H Robinson³, T Folks¹, S Butera¹, and Dennis Ellenberger¹ These findings demonstrate that there is no evidence of replication-competent virus in the 4 protected monkeys and that the HIV-1 DNA/MVA vaccine construct provides complete protection from infectious virus in a subset of monkeys in the repeated dose SHIV SF162P3 challenge model.
467	IMMUNIZATION WITH VACCINIA VIRUS INDUCES POLYFUNCTIONAL T-CELL RESPONSES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 467) Melissa Precopio¹, M Betts², J Parrino¹, R Bailer¹, M Roederer¹, B Graham¹, and R Koup¹ Our results indicate that different vaccine vectors induce different T-cell functional profiles that may be important in protection against virus challenge.
468	ENHANCED DIVERSITY AND MAGNITUDE OF CELLULAR IMMUNE RESPONSES ELICITED BY A NOVEL ENGINEERED HIV-1 SUBTYPE B SYNTHETIC EARLY TRANSMITTER CONSENSUS-BASED ENVELOPE DNA VACCINE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 468) Jian Yan, H Yoon, S Kumar, M Ramanathan, K Muthumani, S Calarota, A Dai, N Corbitt, J Boyer, and D Weiner EY2E1-B could serve as an immunogen that increases both the magnitude and breadth of CTL responses as a DNA vaccine cassette, suggesting that such synthetic immunogens deserve further examination for their potential to serve as a component antigen in a HIV vaccine cocktail.
469	PROTECTION AGAINST SIMIAN/HUMAN IMMUNODEFICIENCY VIRUS 89.6P REPLICATION IN MACAQUES FOLLOWING CO-IMMUNIZATION WITH SHIV ANTIGEN AND AN OPTIMIZED RHESUS IL-15 PLASMID IS NOT ASSOCIATED WITH IFN-γ SECRETION BY T LYMPHOCYTES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 469) J Boyer¹, M Kutzler¹, S Kumar¹, R Parkinson¹, G Vansant², P Silvera³, Z Israel⁴, J Monforte², J Eldridge⁴, and David Weiner¹ This study demonstrates that DNA vaccination with pmacIL-15-opt immunoadjuvant can control SHIV-89.6P infection. Furthermore, this study provides insight into the correlates of protection for an HIV-1 prophylactic vaccine.
470	NOVEL BIODEGRADABLE NANOPARTICLES INDUCE DENDRITIC CELL MATURATION AND POTENT CELLULAR IMMUNITY TO PARTICLE-ASSOCIATED HIV-1 ANTIGENS IN MICE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 470) Xin Wang^1,2, T Uto^1,2, T Akagi^2,3, M Akashi^2,3, and M Baba^1,2 Our biodegradable NP induce DC maturation, improve antigen uptake, and, more importantly, generate strong cellular immune responses to protein-based antigens. Thus, γ-PGA NP carrying various HIV-1 proteins (e.g., AIDSVAX) should be further perused for their potential as a novel vaccine candidate.
471	INCREASED IMMUNOGENICITY AND EFFICACY OF IMMUNODEFICIENCY VIRUS-LIKE PARTICLES PSEUDOTYPED WITH THE G PROTEIN OF VESICULAR STOMATITIS VIRUS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 471) Seraphin Kuate¹, C Stahl-Hennig², H Stoiber³, G Nchinda^1,4, S Bredl⁵, P Racz⁶, K Tenner-Racz⁶, R Steinman⁴, R Wagner⁵, and K Ueberla¹ Although we only observed persistent control of viremia in a small number of SIV-challenged monkeys after a long-term vaccination regimen, the VSV-G induced enhancement of humoral and cellular immune responses could be of broad interest in the demanding HIV vaccine field and be a more widely applicable approach to improve vaccines against other infectious diseases.
472	FOAMY VIRUS VECTORS PERSISTENTLY EXPRESS HIGH LEVELS OF HIV-1 GAG: POTENTIAL FOR HIV VACCINES AND GENE THERAPY VECTORS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 472) David Hardy^1,2, C Liu¹, Y Xie², T Folks³, and I Chen² FV vectors can successfully transduce rodent and human epithelial and hematopoietic cell lines with detectable integrated p24 DNA, mRNA, and protein expression as long as 6 weeks post-infection. Infection of MDDC, although low-level, is promising. Persistent infection of these or human immune cells may act as a persistent source of HIV-1 immunogen for vaccine strategies.
473	COMPUTATIONAL MEANS OF GENERATING IMMUNOGEN CANDIDATES THAT HAVE A HIGH DEGREE OF CROSS-REACTIVITY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 473) David Nickle¹, M Rolland¹, M Seligman¹, W Deng¹, D Heckerman², J Mullins¹, and N Jojic² This method potentially allows us to remove decoy mutations and develop a vaccine that targets potential escape routes. Using an onion analogy: the center of the onion is the COT and the skin is the sequences of the circulating strains. We are building onto the central sequence the intermediate layers of the onion for which we hope will lead to the highest degree of cross-reactivity possible in an immunogen.
474	DETECTION OF N-LINKED GLYCOSYLATION SITE INTERACTIONS IN HIV-1 ENVELOPE PROTEINS BY BAYESIAN NETWORK ANALYSIS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 474) Art Poon¹, F Lewis², and S Frost¹ Maximum likelihood analysis of alternative evolutionary models for PNGS in a multiple alignment of HIV-1 env CDS supports a covarion model, implying that dependencies among PNGS modify evolutionary rates over time. Bayesian network analysis identifies interdependencies among multiple sites, including a long-range interaction between the gp120 ectodomain and the gp41 intra-cytoplasmic tail.
Session 82—Poster Abstracts HIV Vaccines: Clinical Trials and Mathematical Models of Efficacy
475	VACCINATION WITH MVA NEF IS IMMUNOGENIC AND SAFE IN HIV-1-NEGATIVE VOLUNTEERS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 475) Thomas Harrer¹, P Chaplin², J Hain¹, J Vollmar², B Petzold², A Handley², S Bergmann¹, K Eismann¹, M Rittmaier¹, and E Harrer¹ MVA-Nef was safe and immunogenic in uninfected subjects and induced a Nef-specific T-cell response in 9 of 14 (64 %) healthy volunteers, whereas Nef-specific antibodies could be detected in 14%. All subjects developed a strong MVA-specific T-cell and antibody response.
476	A RANDOMIZED OPEN PHASE I TRIAL TO ASSESS THE SAFETY AND IMMUNOGENICITY OF 4 MG DNA-C FOLLOWED BY NYVAC-C COMPARED WITH NYVAC-C ALONE IN HEALTHY HIV-NEGATIVE VOLUNTEERS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 476) Pierre-Alexandre Bart¹, T Barber², M Khonkarly¹, D Ciuffreda¹, S Burnet¹, W Stöhr³, M Cowen², S McCormack³, G Pantaleo¹, J Weber², and EuroVacc Programme To date, 4-mg DNA-C and NYVAC-C appears to be safe and sufficiently well tolerated. Vaccine-induced HIV-1-specific interferon (IFN)-γ-secreting T cells will be assessed by ELISpot.
477	RECOGNITION OF AUTOLOGOUS HIV-1 VARIANTS BY CTL IN HIV-1-INFECTED SUBJECTS AFTER VACCINATION WITH AN MVA-NEF VECTOR Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 477) Thomas Harrer¹, M Bäuerle¹, P Chaplin², J Hain², B Petzold², K Eismann¹, S Bergmann¹, M Rittmaier¹, S Müller¹, and E Harrer¹ In several patients, we observed CTL recognition of autologous viral variants despite the occurrence of mutations that confer CTL escape in other patients. This suggests that the CTL response can adapt to HIV-1 sequence variation within CTL epitopes as long as the anchor positions remain conserved. Therefore, for the development of polytope vaccines it is important to focus on CTL epitopes with conserved anchor amino acids.
478	CLINICAL SAFETY OF HIV LIPOPEPTIDES USED AS VACCINES IN HEALTHY VOLUNTEERS AND HIV-INFECTED ADULTS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 478) Christine Durier¹, O Launay², V Meiffrédy¹, Y Saïdi¹, D Salmon², Y Lévy³, J G Guillet⁴, G Pialoux⁵, and J P Aboulker¹ These data support that reactogenicity and systemic safety of HIV lipopeptide vaccines are acceptable both in healthy volunteers and HIV-infected adults.
479	PREDICTING THE EFFECT OF A PARTIALLY EFFECTIVE HIV VACCINE AND SUBSEQUENT RISK BEHAVIOR CHANGE ON THE HETEROSEXUAL HIV EPIDEMIC IN DEVELOPING COUNTRIES: A SOUTH AFRICAN EXAMPLE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 479) Kyeen Mesesan¹, D Owens², E Vardas³, G Gray³, J McIntyre³, and D Paltiel¹ Even modestly effective HIV vaccines can confer enormous benefits in terms of HIV infections averted and decreased HIV prevalence. However, these findings are sensitive to assumptions regarding the influence of vaccination on subsequent risk behavior. For South Africa and other countries with similar epidemic profiles, programs to reduce risk behavior may be important components of successful vaccination programs.
480	ESTIMATING THE BENEFIT OF A HIV-1 VACCINE THAT REDUCES VIRAL LOAD SET-POINT Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 480) Swati Gupta¹, L Jacobson², C Rinaldo³, J Phair⁴, B Jamieson⁵, J Margolick², D Mehrotra¹, M Robertson¹, and W Straus¹ The time to key clinical events in the course of HIV-1 disease progression was significantly extended for those with early HIV-1 RNA 0.5-1.25 log₁₀ copies/mL lower than the reference group. For those with a viral set-point of 3000 vs 30,000 copies/mL, the relative time to clinical events examined was approximately double or higher, even for those events that occur earlier in disease progression. By quantifying the anticipated clinical benefits associated with a reduction in viral set-point, these findings provide support for the use of virologic endpoints in HIV-1 vaccine trials.
481	EFFICACY OF INTRADERMAL ADMINISTRATION OF HEPATITIS B VACCINE IN HIV-INFECTED NON-RESPONDERS TO 2 COURSES OF INTRAMUSCULAR HBV VACCINE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 481) Stephen Shafran, L Mashinter, A Lindemulder, G Taylor, and I Chiu In HIV-infected subjects who fail to respond to 2 series of recombinant HBV vaccine administered intramuscularly, the administration of HBV vaccine intradermally results in an initial anti-HBs response in about half, but this response wanes within 1 year.
Session 83—Poster Abstracts Therapeutic Vaccination
482	FOLLOW-UP OF A PHASE I TRIAL OF THE INFUSION OF AUTOLOGOUS EX VIVO CD3/CD28 CO-STIMULATED AND EXPANDED CD4+T CELLS IN HIV-1 INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 482) Wendy Bernstein^1,2, B Levine³, N Aronson^1,4, C Liebig², H Flaks⁵, and C June³ The previously reported increases in CD4 counts, percentage of CD4, and CD4:CD8 ratios now appear durable at a median of 3.3 years after completing adoptive immunotherapy infusions. Disease stability is suggested by the constant rate of HIV-related events. These data support the premise that infusions of ex vivo co-stimulated and expanded CD4+ T cells can contribute to maintain immune homeostasis in HIV-infected subjects.
483	MEMORY T-CELL RESPONSES INDUCED BY TOPICAL DERMAVIR VACCINE ARE ENHANCED BY IL-7 AND IL-15 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 483) S Calarota¹, A Dai¹, J Trocio², F Lori², D Weiner¹, and Julianna Lisziewicz³ These results demonstrate that IL-7 and IL-15 remarkably enhance memory T cells induced by DermaVir. These cytokines were effective both after DermaVir prime and DermaVir+vaccinia prime-boost regimens. Since the goal of therapeutic vaccination is to induce memory T cells that can expand to effectors in the presence of HIV, IL-7 and IL-15 represent important adjuvant candidates.
484	AUTOLOGOUS NEF RNA HIV-1 ELECTROPORATED DC ENHANCES THE DETECTION OF CD8-SPECIFIC PROLIFERATIVE RESPONSES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 484) Oleg Yegorov¹, B Yassine-Diab¹, T Baumgartner¹, R Boulassel², J P Routy², D Healay³, I Tcherepanova³, C Nicolette³, and R P Sekaly¹ We show that the use of autologous NEF mRNA permits the detection of the proliferative capacity of specific CD8+ T cells, a significant factor in HIV vaccine design and development.
485	DNA IMMUNOTHERAPY AND IL-12 SUPPRESSES VIRAL REPLICATION FOLLOWING THE CESSATION OF ANTIRETROVIRAL DRUGS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 485) J Boyer¹, S Kumar¹, R Halwani², R Parkinson¹, L Wu¹, G Pavlakis³, B Felber³, M Lewis⁴, R P Sekaly², and David Weiner¹ This study demonstrates that IL-12 as an immunoadjuvant enhanced immune responses when co-delivered with SIV DNA-expressing vaccines. In addition, an enhanced immune response following DNA immunotherapy can affect viral replication.
486	DENDRITIC CELL-HIV PEPTIDE THERAPEUTIC VACCINATION IS SAFE AND IMMUNOGENIC IN HIV-INFECTED SUBJECTS WITH VIROLOGIC SUPPRESSION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 486) Nancy Connolly¹, S Riddler¹, C Wilson², T Whiteside¹, and C Rinaldo¹ DC vaccination was safe and feasible in HIV-infected subjects on ART with virologic suppression. DC vaccination with selected HLA-A2 peptides was immunogenic in this cohort. Future, larger DC vaccine studies utilizing more broadly reactive antigens and clinical end-points are warranted.
487	QUEST STUDY: FOLLOW-UP AT 1 YEAR POST-STOPPING TREATMENT IN PRIMARY HIV INFECTION SUBJECTS ON LONG-TERM ART RANDOMIZED TO THERAPEUTIC IMMUNIZATION VS PLACEBO Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 487) Sabine Kinloch¹, F Lampe¹, L Perrin², D Cooper³, B Hoen⁴, L E Goh⁵, C Tsoukas⁶, R El-Habib⁷, G Theofan⁸, A Phillips¹, and the QUEST Study Group Safety of our intervention was demonstrated with preserved CD4 counts and absence of deaths or AIDS events in patients on ART ± therapeutic immunization who discontinued ART. Restart of ART occurred mainly because of high viral load. Proportions of subjects fulfilling primary end-point (<1000 copies/mL) decreased at 48 weeks post-stopping with no apparent impact of immunization.
488	CYTOLITIC AND NON-CYTOLITIC ANTIVIRAL MECHANISMS ELICITED BY HIV-1 WHOLE INACTIVATED VACCINE IN HAART-NAÏVE, ASYMPTOMATIC HIV-INFECTED INDIVIDUALS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 488) D Trabattoni¹, A Gori², R Maserati³, G Rizzardini⁴, C Fenizia¹, A Marino¹, F Mazzotta⁵, G Theofan⁶, D Bray⁷, and Mario Clerici¹ Remune elicits both cytolitic and non-cytolitic antiviral mechanisms in ART-naïve, asymptomatic HIV-1-infected subjects. The short duration of the trial did not allow the detection of changes in plasma viremia. Nevertheless, because effector memory reverts to central memory in the presence of low antigenic load, these data, along with the stabilization of CD4 counts seen in these individuals, suggest that Remune could lower extraplasmatic (i.e. tissue) HIV viremia.
489	THERAPEUTIC VACCINATION WITH REMUNE INDUCES CD8+ HIV-1-SPECIFIC CYTOTOXIC RESPONSES IN PATIENTS WITH CHRONIC HIV-1 INFECTION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 489) Larissa Valor¹, J Navarro¹, B Santamaria¹, C Rodriguez-Sainz¹, J Carbone¹, J Gil¹, S Moreno², D Podzamczer³, J Gonzalez-Lahoz⁴, and E Fernandez-Cruz¹ Long-term therapeutic vaccination with Remune induces CD8+ HIV-specific cytotoxic responses that correlated negatively with viral load in patients with chronic HIV-1 infection.
Session 84—Poster Abstracts Miscellaneous Immune-Based Therapeutic Approaches to HIV Infection
490	THERAPY OF SHIV-INFECTED MACAQUES WITH ANTISENSE DNA OF IL-4 Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 490) Navneet Dhillon¹, S Dhillon¹, Y Chebloune¹, I Adany¹, Z Li¹, F Villinger², O Narayan¹, and S Buch¹ This is the first demonstration of effective SHIV inhibition in targeted macaque tissues by intravenous injection of cytokine antisense DNA complexed with cationic lipids. The therapeutic effect of the antisense IL-4 suggests indirectly that the acute immunosuppressive disease caused by SHIV is mediated, in part, by IL-4, which causes enhanced virus replication via co-receptor usage, and simultaneously by suppressing anti-viral CD8 T cell responses.
491	IL-21: A NOVEL REGULATOR OF CYTOTOXIC POTENTIAL IN CD8 T CELLS OF HIV-INFECTED PATIENTS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 491) Lesley White¹, N Strbo¹, H Liu¹, M Kolber¹, W Kindsvogel², and S Pahwa¹ These data suggest a potential role for IL-21 in boosting anti-viral immunity by building up intracellular perforin stores, without inducing activation or degranulation of memory CD8 T cells.
492	NATURAL KILLER CELLS AS TARGETS FOR IMMUNE-BASED INTERVENTION IN HIV DISEASE Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 492) Gabriella d'Ettorre¹, M Andreotti², C Andreoni¹, L Zaffiri¹, S Antonucci¹, S Vella², V Vullo¹, and C Mastroianni¹ NK cells derived from HIV viremic and aviremic patients can secrete relevant amounts of IFN-γ and CC chemokine after in vitro treatment with IL-15 alone or in combination with IL-12. The present study indicates that NK cells are an important target for immunotherapeutic agents and provides additional pre-clinical data supporting the great potential of IL-15 in the immune-based interventions in HIV disease.
493	DECREASED FOXP3 EXPRESSION IN CD4+CD25+ T CELLS FROM HIV-1-INFECTED PATIENTS FOLLOWING IL-2 THERAPY AND INTERRUPTION OF HAART Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 493) Sarah Wynne, V Thaker, C Keh, J Shen, C Rehm, R Davey, H Lane, and I Sereti Despite increases in CD4+ T cells and increases in expression of CD25 on both naïve and memory CD4+ T cells, the amount of foxP3 expression was lower following IL-2 therapy and HAART interruption. This suggests that viremia can blunt the preferential expansion of CD4+CD25+ T cells expressing high levels of foxP3.
494	EFFICACY OF RECOMBINANT INTERLEUKIN-2 IN PATIENTS WITH ADVANCED HIV-1 INFECTION AND BLUNTED IMMUNE RESPONSE TO HAART Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 494) Manel Crespo, I Caragol, V Falcó, E Ribera, S Villar Del Saz, A González, I Ocaña, and A Pahissa rIL-2 might be useful in patients with advanced HIV disease showing a blunted immune response to HAART. Our results suggest that rIL-2 leads to the emergence of a CD4+CD25+ T-cell subpopulation that plays an essential role in the homeostasis of the peripheral CD4 T cell pool, with down-regulation of immune activation alongside with the increase in the counts of naïve and recall memory.
495	EFFECTS OF RECOMBINANT HUMAN GROWTH HORMONE ON HIV-1-SPECIFIC T-CELL RESPONSES, THYMIC OUTPUT AND PROVIRAL DNA IN PATIENTS ON ART: 48-WEEK FOLLOW-UP Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 495) N Imami¹, Catherine Burton¹, G Moyle², B Gazzard², and F Gotch¹ The implication of these data is that concomitant administration of rhGH with effective ART results in a dose-dependent reversal of both the CD4 and the CD8 T lymphocyte dysfunction commonly observed in HIV-1+ patients. Such immune-based therapeutic strategies in treated chronic HIV-1 infection may enable the induction of virus-specific CD4 T cells essential for the subsequent “kick-start” and expansion of specific CD8 T cells.
496	EFFECT OF GENETIC HOST FACTORS ON TREATMENT SUCCESS IN HIV-1-INFECTED PATIENTS: IDENTIFICATION OF RESPONDERS AND NON-RESPONDERS BY GNAS GENOTYPING Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 496) Norbert Brockmeyer¹, G Faetkenheuer², S Staszewski³, H Klinker⁴, J Rockstroh⁵, A Potthoff¹, W Siffert⁶, and ESPRIT Study Group and Competence Network HIV/AIDS These data suggest that IL-2-induced CD4 rises are genetically determined and that genotyping the GNAS G(-1211)A polymorphism could identify treatment responders.This finding could be of utmost clinical significance.
497	INTERLEUKIN-15 ENHANCES THE NATURAL KILLER ACTIVITY ACCORDING TO HAART SUPPRESSION OF HIV-1 REPLICATION Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 497) Mauro Andreotti¹, G d'Ettorre², C Andreoni², M Mancini¹, S Antonucci², M Giuliano¹, S Vella¹, V Vullo², and C Mastroianni² Our data suggest that IL-15 is capable of priming cytotolityc activity of NK cells in HIV-infected patients during HAART, suggesting a possible role in immune therapy. In particular, the observed high values of IL-15-primed NK cells LU/10⁷ in viremic HAART patients underline the ability of IL-15 in abolishing the natural immune impairment despite HIV replication.
Session 85—Poster Abstracts New Antiretroviral Agents and Approaches-Preclinical Studies
498	AMIDATE PRODRUG OF A NUCLEOTIDE ANALOG GS9148 ENHANCES THE IN VITRO INTRACELLULAR DELIVERY OF THE ACTIVE DIPHOSPHATE METABOLITE: POTENTIAL FOR CLINICAL EFFICACY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 498) Adrian Ray, J Vela, R Mackman, L Zhang, H Hui, R Pakdaman, A Carey, M Wright, G Rhodes, and T Cihlar Oral administration of GS9148 amidate prodrug to dogs resulted in a substantial accumulation of GS9148-DP in PBMC. Clinically effective concentrations of GS9148-DP in patient PBMC are expected to be readily achieved following once daily oral administration of the GS9148 prodrug at doses <2 mg/kg.
499	INTRACELLULAR METABOLISM OF 2'-DEOXY-4'-C-ETHYNYL-2-FLUOROADENOSINE, A NOVEL 4'-C-ETHYNYL NUCLEOSIDE ANALOG POTENT AGAINST MULTIDRUG-RESISTANT HIV-1 VARIANTS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 499) Hirotomo Nakata¹, Y Koh¹, E Kodama², G Yang³, S Kohgo⁴, H Hayakawa⁴, H Ohrui⁵, M Matsuoka², Y C Chen³, and H Mitsuya^1,6 E2FdA possesses long intracellular T_1/2 of its TP form (>12 hours) and exerts minimal inhibition to DNA polymerase-γ. The present data suggest that once daily dosing schedule of E2FdA could be possible with few side effects and warrant that E2FdA be further developed as a potential therapeutic for HIV-1 infection.
500	MUTATIONAL PATTERNS ASSOCIATED WITH REDUCED AND INCREASED SUSCEPTIBILITY TO NcRTI IN >6000 CLINICAL HIV-1 ISOLATES Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 500) Dirk Jochmans¹, H Van Marck¹, M Van Ginderen¹, I De Baere¹, P Dehertogh¹, A Peeters¹, B Kesteleyn¹, T Pattery², P Mc Kenna², and K Hertogs¹ Analysis of HIV-1 clinical isolates and SDM strains showed that the combination of RT mutations M184V and Y115F is associated with a decreased susceptibility to NcRTI. In addition, amino acid change K65R was found to restore the susceptibility of M184V carrying viruses to NcRTI. These data, together with the observation that neither TAM, nor the 69ins-MDR complex, nor the Q151M-MDR complex influences susceptibility to NcRTI, warrant further exploration of this novel class of HIV inhibitors.
501	SPI-256, A HIGHLY POTENT HIV PROTEASE INHIBITOR WITH BROAD ACTIVITY AGAINST MDR STRAINS Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 501) Sergei Gulnik¹, E Afonina¹, M Eissenstat¹, N Parkin², A Japour¹, and J Erickson¹ SPI-256 displays 4- to 50-fold greater in vitro potency than currently approved PI against wild type HIV-1 as judged by IC₅₀ values in PhenoSense assay and maintains potency against highly resistant MDR HIV isolates. This inhibitor represents a potential new antiviral agent for first line as well as salvage therapy.
502	RITONAVIR NANOPARTICLES INHIBIT PRODUCTIVE REPLICATION OF HIV-1ADA IN MDM Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 502) Anuja Ghorpade, K Rao, P Sahoo, S Sahoo, K Borgmann, R Persidsky, and V Labhasetwar The results of our studies thus demonstrate that nanoparticles can be used as a delivery vehicle for anti-HIV drugs. Our future goal is to modify drug-loaded nanoparticles with a TAT peptide to study the transport and central nervous system delivery of anti-HIV drugs.
503	DETERMINATION OF RESISTANCE PROFILE OF GRL-02031, A NOVEL NONPEPTIDIC PROTEASE INHIBITOR CONTAINING A CYCLOPENTANYLTETRAHYDROFURAN MOIETY Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: (abstract no. 503) Yasuhiro Koh¹, H Nakata¹, H Ogata-Aoki¹, M Nakayama¹, S Leschenko², A Ghosh², and H Mitsuya^1,3