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15th Conference on Retroviruses and Opportunistic InfectionsBoston, Massachusetts - February 3-6, 2008 |
Cite as: Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:abstract no. xx
| Session 3—Symposium Scale-up of HIV Prevention in the Developing World |
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| 2 | IMPLEMENTING CIRCUMCISION FOR HIV PREVENTION IN SUB-SAHARAN AFRICA Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:69 (abstract no. 2) Bertran Auvert1, E Marseille2, and J Kahn2 A rapid roll-out of MAMC in Sub-Saharan Africa requires substantial funding and a high number of circumcisers for the first 5 years. These investments are justified by MAMC’s substantial health benefits and the savings that accrue by averting future HIV infections. Lower ongoing costs and continued care savings suggest long-term sustainability. |
| 3 | SCALE-UP OF HIV TESTING IN AFRICA Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:69 (abstract no. 3) Elizabeth Marum In spite of these developments, many barriers remain. Integration of HIV testing into routine medical care in high-prevalence settings is undermined by the severe shortage of health workers, and separate testing services provided by a lay counselor may be the only practical approach in many countries. Partner disclosure remains difficult, and only a few programs have been successful in increasing couple counseling and testing. Continued international and national support for HIV testing in Africa, as well as policy reform and measures to address health manpower shortages, are essential to ensure universal access to knowledge of HIV status. |
| 4 | ART IN AFRICA: BEYOND THE ROLL-OUT Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:69 (abstract no. 4) Gary Maartens The World Health Organization’s 2006 revised guidelines allow for earlier initiation of ART, largely based on symptomatic disease. Initiating ART based on a CD4 threshold of 350 should be considered for pregnant women, but will be unlikely to affect access to ART for other patients. Most countries rely on generic antiretrovirals with stavudine (d4T) in the first-line regimen, but d4T toxicity is increased in women and obese patients, which is common in urban Africa. |
| 5 | PREVENTION OF CERVICAL CANCER IN THE HAART ERA Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:70 (abstract no. 5) Silvia Franceschi Screening for high-risk HPV types would have several advantages over other types of screening: it is more sensitive for high-grade cervical lesions and much less dependent on the quality of the sample, and human judgement than cytology and visual inspection. Importantly, a cheaper reconfiguration of Hybrid Capture™ 2 is in the pipeline. The choice of the cut-off sensitivity of the HPV test is in general very important in screening programs to avoid over-treatment of women with low viral load infections that are probably harmless. This choice is, however, especially difficult among HIV+ women, in whom as much as 85% prevalence of carcinogenic HPV types have been reported. |
| Session 4—Opening Plenary and Keynote Session 13th Annual Bernard Fields Memorial Lecture and 2nd N'Galy-Mann Lecture |
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| 6 | CONTENDING WITH EVOLUTION AND ESCAPE BY HIV Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:70 (abstract no. 6) Douglas Richman The consequence of this capacity to escape cell-mediated immunity and neutralizing antibody is a remarkable genetic and antigenic diversity that has proven an insurmountable barrier to vaccine development. Only fundamental new insights into contending with this diversity will permit the development of an effective vaccine. |
| 7 | A POPULATION-BASED APPROACH TO UNDERSTANDING A VERY CLEVER VIRUS: A BRIEF HISTORY OF HIV RESEARCH AND SERVICES IN THE RAKAI HEALTH SCIENCES PROGRAM, UGANDA Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:70 (abstract no. 7) David Serwadda1, M Wawer2, N Sewankambo3, R Gray2, and for the Rakai Hlth Sci Prgm The Rakai community cohort enables the RHSP to pursue a population-based approach to HIV research and services, facilitating a wide-ranging research program from the molecular to the community level. This has enhanced the understanding of the HIV/AIDS epidemic, of potential interventions, and of the substantial challenges which remain. |
| Session 5—Plenary Morbidity and Mortality in the HAART Era |
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| 8 | MORBIDITY AND MORTALITY IN THE HAART ERA Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:71 (abstract no. 8) Andrew Phillips Data from all these sources have their limitations but taken together evidence for a link between HIV and risk of serious non-AIDS diseases is appreciable. Possible approaches to further reducing the clinical burden will then be outlined, including the potential need to consider earlier ART initiation. It is important to better understand the epidemiology of residual HIV-associated disease in the HAART era so that suitable potential new interventions can be designed. |
| Session 6—Plenary Searching the Genome for Determinants of Response to HIV |
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| 9 | SEARCHING THE GENOME FOR DETERMINANTS OF RESPONSE TO HIV Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:71 (abstract no. 9) David Goldstein Here I report on the extension of these studies and on progress and plans for further studies focused on viral control in African Americans, the determinants of susceptibility to infection, and the genomic determinants of response to vaccination. |
| Session 7—Oral Abstracts Epidemiology of SIV/HIV Infection and AIDS-related Malignancies |
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| 10 | GEOGRAPHIC DISTRIBUTION OF SIVgor IN WILD-LIVING GORILLAS FROM CAMEROON Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:72 (abstract no. 10) Cecile Neel1,2, F Van Heuverswyn1, E Mpoudi Ngole2, Y Li3, B Keele3, F Liegeois1, C Butel1, E Delaporte1, B Hahn3, and M Peeters1 New and previous field studies indicate an uneven distribution of SIVgor in western lowland gorillas (G. g. gorilla) throughout southern Cameroon and suggest that ape reservoir(s) that gave rise to HIV-1 O could occur outside Cameroon. However, we identified an area of high SIVgor endemicity in southwest Cameroon. More eastern gorillas need to be tested to allow significant conclusions about their SIV status. |
| 11 | DIAGNOSIS AND MONITORING OF HIV-1 GROUP O INFECTIONS IN CAMEROON Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:72 (abstract no. 11) Aurelia Vessiere1, D Rousset1, M Leoz2, A Depatureaux2, F Simon3, and J C Plantier2 In our study, prevalence of HIV-O infections was low (1.3%) with nearly 10% of M/O dual infections. Monitoring of HIV-O infections can be easily done with specific tools. However, the high natural polymorphism of HIV-O pol gene underlines the need for an adapted resistance interpretations algorithm. Efficacy of NNRTI on 181Y strains must be studied, especially in Cameroon where nevirapine (NVP) is widely used in first-line regimen and therapeutic options remain limited. |
| 12 | NEW AND OLD COMPLEX RECOMBINANT HIV-1 STRAINS ENTERING IN FRANCE AMONG PATIENTS WITH PRIMARY INFECTION IN 2004 TO 2006: THE FRENCH ANRS CO06 PRIMO COHORT STUDY Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:73 (abstract no. 12) P Frange1, J Galimand1, M Peeters2, C Goujard3, C Deveau4, V Avettand - Fenoel1, F Souala5, L Meyer4, C Rouzioux1, and Marie-Laure Chaix1 This study illustrates the increasing HIV-1 diversity in France, with description of 3 new complex mosaic strains, 1 new CRF and 2 URF. CRF27 and MAL-like sequences are old HIV-1 strains which are rare in their region of origin but may have a founder effect in France. Our results strengthen the French guidelines recommending genotypic resistance tests in patients with primary HIV-1 infection for the surveillance of the frequency of resistant strains, but also for surveillance of HIV-1 diversity. |
| 13 | RECENT PHYLODYNAMICS OF THE HIV EPIDEMIC AMONG MSM IN THE UK Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:73 (abstract no. 13) Gareth Hughes1, A Leigh Brown1, A Rambaut1, S Lycett1, F Lewis2, E Fearnhill3, and UK Collaborative Group on HIV Drug Resistance Reconstruction of transmission clusters from the U.K. HIV epidemic using a dated phylogeny approach has shown the episodic nature of HIV epidemiology in men who have sex with men (MSM). There is evidence of multiple clusters of transmissions dating to the late 1990s, a period when HIV prevalence is known to have doubled. The quantitative description of the transmission dynamics among MSM suggests “small-world” network structures exist in this group and will be important for parameterization of epidemiological models and assisting to design intervention strategies. |
| 14 | CHANGES OVER TIME IN THE RISK OF DEATH FOLLOWING HIV SEROCONVERSION COMPARED WITH MORTALITY IN THE GENERAL POPULATION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:73 (abstract no. 14) Kholoud Porter1, O Hamouda2, M Sannes3, F Boufassa4, A Johnson5, S Walker1, and CASCADE Collaboration Mortality rates for HIV-infected persons have become much closer to general mortality rates since the introduction of HAART. HIV-infected persons in developed countries now appear to experience similar rates to their uninfected counterparts in the first 5 years from infection, though a mortality excess remains as HIV infection duration lengthens. |
| 15 | IMMUNODEFICIENCY AND RISK OF AIDS-DEFINING AND NON-AIDS-DEFINING CANCERS: ANRS CO3 AQUITAINE COHORT, 1998 TO 2006 Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:74 (abstract no. 15) M Bruyand1,2, R Thiebaut1,2,3,4, S Lawson-Ayayi1,2, P Joly3,4, A Sasco5, J L Pellegrin2,4,6, D Neau2,4,6, P Morlat1,2,4,6, G Chene1,2,4, Fabrice Bonnet1,2,4,6, and Groupe d'Epidémiologie Clinique du SIDA en Aquitaine (GECSA) A longer exposure to uncontrolled HIV RNA was associated with a higher risk of AIDS-defining cancers, independently of CD4 count. Moreover, prolonged immunosuppression was associated with a higher risk of cancers of both types, regardless of the CD4 count threshold considered. ART should aim at reaching and maintaining the CD4 count >500/mm3 to prevent the occurrence of all cancers, in addition to other prevention policies. |
| 16 | INSUFFICIENT VIRUS SUPPRESSION DURING HAART IS A STRONG PREDICTOR FOR THE DEVELOPMENT OF AIDS-RELATED LYMPHOMA: GERMAN CLINSURV COHORT Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:74 (abstract no. 16) Alexander Zoufaly1, H J Stellbrink2, M an der Heiden3, C Kollan3, J van Lunzen1, O Hamouda3, and CLINSURV Study group In addition to known risk factors, MSM status and incomplete viral suppression during HAART were strong predictors for the development of AIDS-related lymphoma in this analysis. As viremia represents the only potentially modifiable risk factor identified, a clinical strategy to optimize HAART at any time-point with respect to viral suppression could help to minimize the incidence of AIDS-related lymphoma. |
| Session 8—Oral Abstracts Viral Pathogenesis and Immune Surveillance |
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| 18 | PATTERNS OF CD8+ IMMUNODOMINANCE MAY INFLUENCE THE ABILITY OF MAMU-B*08+ MACAQUES TO NATURALLY CONTROL SIVmac239 REPLICATION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:75 (abstract no. 18) John Loffredo1, A Bean1, D Beal1, E Leon1, S Piaskowski1, S Musani2, E Rakasz1, N Wilson1, D Allison2, and D Watkins1 Natural containment of AIDS virus replication in Mamu-B*08+ macaques may be related to a combination of immunodominance and viral escape from CD8+ T cell responses. |
| 19 | CD20+ CELL DEPLETION RESULTS IN ABBREVIATED CELL-MEDIATED IMMUNE RESPONSES, HIGHER VIRAL SET-POINTS AND SHORTENED SURVIVAL IN SIV-INFECTED PIGTAILED MACAQUES Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:75 (abstract no. 19) Lu-Ann Pozzi, D Pauley, S Sato, H Knight, D Walsh, A Carville, W Johnson, S Westmoreland, and S O'neil Overall, CD20-depleted SIVsmmFGb-infected macaques had shortened survival post-inoculation, with 3 of 4 developing SIVE and AIDS by 10 weeks post-inoculation. All CD20-depleted animals failed to mount or maintain SIV-specific CMI responses, suggesting a correlation between B cell function and CD8+ T cell responses in the control of primate lentivirus infections. |
| 20 | HUMORAL IMMUNE RESPONSES HAVE LITTLE EFFECT ON CONTROLLING VIREMIA DURING SIVagm INFECTION OF AFRICAN GREEN MONKEYS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:76 (abstract no. 20) Thaidra Gaufin1, M Pattison1, C Stoulig1, R Gautam1, M Barnes1, C Monjure1, M Marx1, D Montefiori2, C Apetrei1, and I Pandrea1 Our study shows that humoral immune responses play no significant role in the control of SIV viral replication during acute and chronic SIVagm infection in the natural host. |
| 21aLB | EXPERIMENTALLY INDUCED IMMUNE ACTIVATION IN NATURAL HOSTS OF SIV RESULTS IN SIGNIFICANT INCREASES IN VIRAL REPLICATION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:76 (abstract no. 21aLB) Ivona Pandrea, C Coleman, T Gaufin, R Gautam, M Pattison, C Monjure, A Lackner, and C Apetrei We report the first successful experiment aimed at inducing immune activation in a natural host of SIV. Also, our results provide for the first time compelling proof-of concept that induction of immune activation during chronic SIV infection results in significant increases in viral replication, thus supporting the concept that immune activation is a key factor in disease progression during HIV/SIV infection. |
| 21bLB | DEPLETION OF CD8+ T CELLS DOES NOT CHANGE THE IN VIVO LIFE SPAN OF INFECTED CELLS DURING PATHOGENIC SIV INFECTIOIN OF RHESUS MACAQUES Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:76 (abstract no. 21bLB) Nichole Klatt1,2, E Shudo3, A Ortiz1, J Engram1, S Gordon1,2, B Lawson2, J Else2, J Schmitz4, A Perelson3, and G Silvestri1 During pathogenic SIVmac239 infection of rhesus macaques the in vivo lifespan of infected cells is similar in the presence or absence of CD8+ T cells. These data suggest that CTL do not have a major impact in determining the lifespan of infected cells during pathogenic SIV infection of rhesus macaques. |
| 22 | FUNCTIONALITY OF HIV-1-SPECIFIC CD8+ T CELLS IS DEPENDENT ON ANTIGEN LOAD AND SEQUENCE DIVERSIFICATION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:77 (abstract no. 22) Hendrik Streeck1, Z Brumme1, M Anastario2, K Cohen1, J Jolin1, G Alter1, A Meier1, T Allen1, B Walker1, and M Altfeld1 These data suggest that the poly-functionality of CD8+ T cell responses is determined by the persistence of antigen and stress the importance of evaluating autologous viral sequence in studies aimed at investigating the relationship between virus-specific immunity and associated pathogenesis. |
| 23 | KINETICS OF ESCAPE WITHIN HLA-RESTRICTED CTL EPITOPES IN THE FIRST YEAR OF HIV INFECTION IS CONSISTENT WITH EARLY IMMUNODOMINANT CTL RESPONSE PATTERNS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:77 (abstract no. 23) Zabrina Brumme1, C Brumme1, H Streeck1, J Carlson2,3, M Markowitz4,5, H Jessen6, A Kelleher7, M John8, D Heckerman2, and B Walker1,9 Marked differences in the kinetics of escape within CTL epitopes correlate with frequency of epitope targeting during primary infection. The finding that certain HLA alleles remain protective despite rapid selection of mutations within targeted epitopes underscores our need to assess the consequences of CTL-driven evolution on HIV disease progression. The inclusion of rapidly selected escape variants into immunogen design deserves consideration. |
| 24 | INTRACELLULAR EPITOPE STABILITY CONTRIBUTES TO HIV EPITOPE HIERARCHY AND CAN BE ALTERED TO MODULATE EPITOPE PRESENTATION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:77 (abstract no. 24) E Lazaro1, P Stamegna1, D Heckerman2, B Walker1,3, and Sylvie Le Gall1,3 This is a first demonstration of a new factor involved in HIV epitope hierarchy, namely, the critical role of epitope intracellular stability. These data also show that epitope presentation can be modulated through alteration of intracellular epitope stability. We propose that changes in epitope sequences at non-essential positions may offer novel way to optimize epitope presentation from vaccine vectors. |
| 25 | MAPPING ESCAPE MUTATIONS ARISING UNDER HLA-RESTRICTED CTL SELECTION PRESSURE IN HIV-1 GAG: CORRELATIONS WITH PLASMA VIRAL LOAD AND CD4 COUNT IN UNTREATED CHRONIC INFECTION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:78 (abstract no. 25) Chanson Brumme1, I Tao2, S Szeto2, Z Brumme1, J Carlson3,4, N Frahm1, R Hogg5,6, B Walker1,7, D Heckerman3, and R Harrigan2,8 We identified in vivo HLA-associated Gag escape patterns associated with measurable increases in plasma viral load, as well as lower CD4 counts. Results support the design of CTL-based vaccine strategies emphasizing Gag, which incorporate information on common escape pathways. |
| Session 9—Oral Abstracts Prevention Strategies |
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| 26 | COMPREHENSIVE PRE-CLINICAL ASSESSMENT OF MICROBICIDE SAFETY USING IN VITRO AND MURINE MODELS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:78 (abstract no. 26) Pedro Mesquita, S Wilson, N Cheshenko, M Keller, B Galen, and B Herold Together, these findings provide a biological explanation that may have contributed to the failed cellulose sulfate clinical trial and indicate tenofovir safety. These data suggest the inclusion of the models presented in the preclinical evaluation of candidate microbicides. |
| 27LB | PROTECTIVE EFFECT OF VAGINAL LACTOBACILLUS ON GENITAL HIV-1 RNA CONCENTRATIONS: LONGITUDINAL DATA FROM A US COHORT STUDY Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:79 (abstract no. 27LB) Jane Hitti1, K Paul1, K Agnew1, R Gausman1, D Lockhart1, S Cohn2, A Luque2, and R Coombs1 1Univ of Washington, Seattle, US; 2Univ of Rochester, NY, US These prospective, longitudinal data demonstrate that acquisition of H202+ Lactobacillus is associated with a significant reduction in vaginal HIV load, while loss of H202+ Lactobacillus results in an increase in vaginal HIV load. These findings may have relevance for secondary prevention strategies. |
| 28LB | TRIAL OF MALE CIRCUMCISION: PREVENTION OF HSV-2 IN MEN AND VAGINAL INFECTIONS IN FEMALE PARTNERS, RAKAI, UGANDA Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:79 (abstract no. 28LB) Aaron Tobian1, D Serwadda2, T Quinn1,3, G Kigozi4, S Reynolds1,3, F Makumbi4, T Suntoke1, S Watya5, M Wawer1, and R Gray1 Male circumcision prevents HSV-2 acquisition in men and reduces rates of GUD, trichomonas, and BV in their female partners. These effects of circumcision may influence the protective effect of circumcision on HIV acquisition. |
| 29 | 3-YEAR FOLLOW-UP OF SEXUAL BEHAVIOR AND HIV TRANSMISSION RISK OF PERSONS TAKING ART IN RURAL UGANDA Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:79 (abstract no. 29) Rebecca Bunnell1, J Ekwaru1, R King1, S Bechange1, D Moore2, K Khana1, W Were1, A Coutinho3, J Tappero1, and J Mermin1 Despite increased sexual activity and a small waning of behavioral risk reduction among HIV-infected Ugandans over 3 years of therapy, risky sex remained lower than baseline levels and ART provision was associated with reduced estimated HIV transmission risk. Integrated ART and prevention programs may reduce HIV transmission in Africa. Programs should consider on-going support for prevention interventions. |
| 30 | EFFECT OF A NOVEL BEHAVIORAL INTERVENTION TO PROMOTE CONDOM USE AMONG FEMALE SEX WORKERS ALONG LAGOS, NIGERIA –COTONOU, BENIN INTERNATIONAL BORDER Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:80 (abstract no. 30) Olusegun Busari, O Busari, G Oligbu, and HIV STUDY GROUP The study shows that this novel behavioral intervention to promote condom use has significant positive influence on FSW, particularly those who are not IDU. It also demonstrates a need for intervention that focuses on addressing issues specific to FSW IDU and sharing of injection equipments using effective culturally sensitive methods. Thus, there is urgent need for holistic approach to curbing the dual problems of HIV and intravenous drug use among FSW in Nigeria and Benin. |
| 31 | SEROSORTING, BUT NOT SEROPOSITIONING, IS ASSOCIATED WITH DECREASED RISK OF HIV SEROCONVERSION IN THE EXPLORE STUDY COHORT Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:80 (abstract no. 31) Susan Philip1, D Donnell2, X Yu2, E Vittinghoff3, and S Buchbinder1 High levels of seropositioning and serosorting were practiced by a sizable minority of MSM in all demographic categories. Our data provide no evidence that seropositioning has any substantive effect against HIV acquisition. In contrast, serosorting was associated with decreased risk of HIV infection, and was the more common strategy, possibly reflecting the intervention counseling emphasis on condom use. Because previous analyses in this and other datasets clearly point to increased risk associated with unprotected sex with multiple HIV– partners, additional models will address whether the protective effects of serosorting can be overcome with larger numbers of partners. |
| 32LB | HSV-2 SUPPRESSIVE THERAPY FOR PREVENTION OF HIV ACQUISITION: RESULTS OF HPTN 039 Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:80 (abstract no. 32LB) Connie Celum1, A Wald1, J Hughes1, J Sanchez2, S Reid3, S Delaney-Moretlwe4, F Cowan5, J Fuchs6, B Koblin7, L Corey8, and HPTN - 039 In HPTN 039, with excellent retention and adherence to twice-daily study drug, daily suppressive therapy with standard doses (400 mg twice daily) of acyclovir did not reduce HIV acquisition among HSV-2+ women and MSM. However, the incidence of GUD was reduced. Thus, acyclovir (400 mg twice daily) suppresses HSV-2, but does not prevent HIV acquisition. Further research is needed to elucidate the disparity between extensive data on epidemiologic and biologic interactions between HSV-2 and HIV and these trial results. |
| 33LB | TRIAL OF MALE CIRCUMCISION IN HIV+ MEN, RAKAI, UGANDA: EFFECTS IN HIV+ MEN AND IN WOMEN PARTNERS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:81 (abstract no. 33LB) Maria Wawer1, G Kigozi2, D Serwadda3, F Makumbi3, F Nalugoda2, S Watya4, D Buwembo2, V Ssempijja2, L Moulton1, and R Gray1 Male circumcision was safe and reduced GUD in HIV+ men. There were no direct HIV benefits to women but, potentially, an increased risk of transmission with early resumption of sex. This has programmatic implications: HIV+ men might seek male circumcision as services roll out, necessitating appropriate education and follow-up. |
| Session 10—Oral Abstracts New Antiretrovirals and Clinical Trials |
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| 34 | STRUCTURE OF HIV-1 CAN IN COMPLEX WITH CAP-1, AN ASSEMBLY INHIBITOR Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:81 (abstract no. 34) Brian Kelly1, S Kyere2, I Kinde2, C Tang2, B Howard3, H Robinson4, W Sundquist1, M Summers2, and C Hill1 Small molecules of the CAP family can bind in a hydrophobic pocket located between CAN helices 1, 2, 4, and 7 that is not observed in the native CAN structure. CAP binding blocks capsid assembly, maturation, and viral infectivity, apparently by disrupting the formation of an essential interface between the CAN and CAC domains. Our work therefore reveals the presence of a previously unrecognized inhibitor binding pocket and can help guide optimization of inhibitors that can bind in this site. |
| 35 | A PROSPECTIVE, RANDOMIZED, CONTROLLED, OPEN-LABEL TRIAL EVALUATING THE EFFECT OF THERAPEUTIC DRUG MONITORING AND PROTEASE INHIBITOR DOSE ESCALATION ON VIRAL LOAD RESPONSES IN ANTIRETROVIRAL-EXPERIENCED, HIV-INFECTED PATIENTS WITH A NORMALIZED INHIBITORY QUOTIENT Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:82 (abstract no. 35) Lisa Demeter1, H Jiang2, L Mukherjee2, G Morse3, R DiFrancesco3, K Klingman4, L Bacheler5, R DiCenzo3, A Rinehart6, M Albrecht7, and the A5146 Study Team There was no overall benefit of TDM in this study. The inability to increase APV concentration with dose escalation in patients on fos-APV is not understood, but may have contributed to the lack of a detectable TDM effect. TDM may confer more benefit in black and Hispanic patients than white patients, for unclear reasons. Subgroup analyses suggest a TDM effect was obscured by the inclusion of patients with highly PI-resistant HIV. |
| 36 | RE-INITIATION OF ART IN THE CD4-GUIDED ART INTERRUPTION GROUP IN THE SMART STUDY LOWERS RISK OF OPPORTUNISTIC DISEASE OR DEATH Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:82 (abstract no. 36LB) Wafaa El-Sadr and SMART Study Group Following the recommendation to reinitiate ART for patients in the DC group, risk of opportunistic disease or death was significantly reduced. However, less than full reversal of risk for DC compared to VS patients for opportunistic disease or death was noted and non-significant reductions for other major outcomes. This may be attributed, in part, to some patients not initiating ART, lower CD4 counts for DC patients post-January 2006, and long-term sequellae of morbidity pre-January 2006. These findings reinforce our recommendation not to interrupt ART using the CD4-guided strategy evaluated in SMART and may have implications for other ART interruption strategies. |
| 37 | EFFICACY AND SAFETY OF ONCE-DAILY ATAZANAVIR/RITONAVIR COMPARED TO TWICE-DAILY LOPINAVIR/RITONAVIR, EACH IN COMBINATION WITH TENOFOVIR AND EMTRICITABINEIN ARV-NAIVE HIV-1-INFECTED SUBJECTS: THE CASTLE STUDY, 48-WEEK RESULTS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:83 (abstract no. 37) Jean-Michel Molina1, J Andrade-Villanueva2, J Echevarria3, P Chetchotisakd4, J Corral5, N David6, M Mancini7, L Percival7, A Thiry7, and D McGrath7 In treatment-naïve patients, ATV/r demonstrated similar efficacy, a lower incidence of gastrointestinal-related adverse events, and a significantly better lipid profile (TC, triglycerides, non-HDL) compared to LPV/r. In combination with TDF and FTC, both ATV/r and LPV/r were well tolerated with few discontinuations through 48 weeks. |
| 38 | SAFETY AND ACTIVITY OF SCH532706, A SMALL MOLECULE CHEMOKINE RECEPTOR 5 ANTAGONIST IN HIV-1-INFECTED INDIVIDUALS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:83 (abstract no. 38) Sarah Pett1, S Emery1, K MacRae2, R Norris2, M McCarthy3, A Tendlokar3, J Tseng3, K Williams4, and D Cooper1 VCV 30 or 20 mg once daily plus RTV-containing OBT provided sustained viral suppression in treatment-experienced subjects and increased CD4 cell counts regardless of the # of active drugs in OBT. VCV 30 mg showed superior efficacy based on % fully suppressed (<50 copies/mL) and was well tolerated. Phase 3 trials are ongoing. |
| 39LB | VICRIVIROC, A NEXT GENERATION CCR5 ANTAGONIST, EXHIBITS POTENT, SUSTAINED SUPPRESSION OF VIRAL REPLICATION IN TREATMENT-EXPERIENCED ADULTS: VICTOR-E1 48-WEEK RESULTS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:84 (abstract no. 39LB) Barry Zingman1, J Suleiman2, E DeJesus3, J Slim4, M McCarthy5, E Lee5, N Case5, C Mak5, and L Dunkle5 VCV 30 or 20 mg once daily plus RTV-containing OBT provided sustained viral suppression in treatment-experienced subjects and increased CD4 cell counts regardless of the # of active drugs in OBT. VCV 30 mg showed superior efficacy based on % fully suppressed (<50 copies/mL) and was well tolerated. Phase 3 trials are ongoing. |
| 40LB | VIROLOGICAL CORRELATES ASSOCIATED WITH TREATMENT FAILURE AT WEEK 48 IN THE PHASE 3 STUDY OF MARAVIROC IN TREATMENT-NAÏVE PATIENTS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:84 (abstract no. 40LB) J Heera1, M Saag2, P Ive3, J Whitcomb4, M Lewis5, L McFadyen5, J Goodrich1, H Mayer1, E van der Ryst5, and Mike Westby5 CXCR4-using virus at baseline was an important predictor of failure on MVC in this study. As seen with treatment-experienced patients, failure with CXCR4-using virus is an important mechanism associated with virological failure. In these patients viral replication in the presence of only NRTI occurred, resulting in selection of NRTI mutations. |
| 41 | TRENDS IN SECOND VIROLOGIC FAILURE AND PREDICTORS OF SUBSEQUENT MORTALITY AMONG ART-EXPERIENCED PATIENTS: NORTH AMERICAN EXPERIENCE Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:85 (abstract no. 41) Stephen Deeks and North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of the IeDEA The risk of progressing to a second episode of VF on HAART has declined dramatically over the past decade. Patients at highest risk for death after 2nd VF according to these factors should be managed as quickly as possible during VF. |
| Session 14—Oral Abstracts Prevention of Mother-to-Child Transmission |
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| 42LB | EXTENDED INFANT POST-EXPOSURE PROPHYLAXIS WITH ANTIRETROVIRAL DRUGS SIGNIFICANTLY REDUCES POSTNATAL HIV TRANSMISSION: THE PEPI-MALAWI STUDY Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:85 (abstract no. 42LB) Taha Taha1, M Thigpen2, N Kumwenda1, D Hoover3, G Kafulafula4, Q Li1, L Mipando5, K Nkanaunena5, M Fowler6, and L Mofenson7 Daily antiretroviral prophylaxis with NVP or NVP/ZDV for the first 14 weeks of life was safe and significantly reduced risk of postnatal HIV infection at age 9 months compared to single-dose NVP+1 week ZDV, and significantly increased 9 month HIV-free survival. Use of 2 drugs (NVP/ZDV) was not superior to NVP alone in terms of transmission, mortality or HIV-free survival. |
| 43 | EXTENDED-DOSE NEVIRAPINE TO 6 WEEKS OF AGE FOR INFANTS IN ETHIOPIA, INDIA, AND UGANDA: A RANDOMIZED TRIAL FOR PREVENTION OF HIV TRANSMISSION THROUGH BREASTFEEDING Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:86 (abstract no. 43) Jayagowri Sastry1,2,3,4 and The Six Week Extended Dose Nevirapine (SWEN) Study Team Daily NVP from day 8 to 42 of life in breastfed infants of HIV-infected mothers is feasible, as safe, and more effective than single-dose NVP alone in improving HIV-free survival at 6 months of age. |
| 44 | TIMING OF INFECTION IS CRITICAL FOR NEVIRAPINE RESISTANCE OUTCOMES AMONG BREASTFED SUBTYPE C HIV-1-INFECTED INFANTS EXPOSED TO EXTENDED VS SINGLE-DOSE NEVIRAPINE PROPHYLAXIS: THE INDIA SWEN STUDY Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:86 (abstract no. 44) Anitha Moorthy1, A Gupta2, G Sastry3, V Venkatramani4, R Bhosale4, V Kulkarni3, N Gupte3, C Ziemniak2, R Bollinger2, D Persaud2, and on behalf of the India SWEN Study Team Higher rates of NVP resistance were seen in extended-dose NVP-exposed infants infected within 6 weeks of life. However, among infants who escaped early infection, wild type HIV-1 is predominantly transmitted through breast milk. Maternal single-dose NVP receipt, however, did not seem to influence this finding in our study. These results may be important for use of extended-dose NVP prophylaxis for preventing breast-milk transmission and subsequent therapy for infants. |
| 45aLB | PMTCT OF HIV-1 AMONG BREASTFEEDING MOTHERS USING HAART: THE KISUMN BREASTFEEDING STUDY, KISUMU, KENYA, 2003-2007 Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:87 (abstract no. 45aLB) Timothy Thomas1, R Masaba2, R Ndivo2, C Zeh1, C Borkowf3, M Thigpen3, K De Cock1, P Amornkul1, A Greenberg3, M Fowler3, and Kisumu Breastfeeding Study Team Low 12-month infant HIV transmission rates were achieved using maternal HAART from late pregnancy through 6 months of breastfeeding. There was no difference in transmission based on maternal CD4 or regimen. Further assessment–adherence to antiretrovirals, the optimal timing for breastfeeding cessation, HIV-free survival, and drug resistance in maternal and infant HIV isolates–is necessary to determine whether HAART is a feasible, acceptable, safe, and efficacious strategy for PMTCT among breastfeeding women, particularly those not meeting WHO treatment criteria. |
| 45b | THE TEmAA ANRS 12109 PHASE II TRIAL, STEP 1: TOLERANCE AND VIRAL RESISTANCE AFTER SINGLE-DOSE NEVIRAPINE AND SHORT-COURSE OF TENOFOVIR DISOPROXIL FUMARATE AND EMTRICITABINE TO PREVENT MOTHER-TO-CHILD TRANSMISSION OF HIV-1 Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:87 (abstract no. 45b) Elise Arrive1, M L Chaix2, E Nerrienet3, S Blanche4, C Rouzioux2, J McIntyre5, P Coffie6, K Sim7, D Ekouevi6, and F Dabis1 A TDF/FTC combination for PMTCT appears to be well tolerated in women and exposed newborns: 7 days of postpartum TDF/FTC exposure seem to extend the suppression of viral replication avoiding NVP-resistance mutations. |
| 46 | DURATION AND PATTERN OF BREASTFEEDING AND POSTNATAL TRANSMISSION OF HIV: POOLED ANALYSIS OF INDIVIDUAL DATA FROM A WEST AND SOUTH AFRICAN COHORT STUDY Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:88 (abstract no. 46) Renaud Becquet1,2,3, R Bland1,4, V Leroy2,3, N Rollins1,5, D Ekouevi2,3,6, A Coutsoudis5, F Dabis2,3, H Coovadia7, R Salamon2,3, and M L Newell1,8 Breastfeeding duration is a major determinant of postnatal HIV transmission, and safe alternatives to breastmilk beyond 6 months are urgently needed. The postnatal-transmission risk was not different in exclusively and predominantly breastfed children, and we confirm the negative effects of mixed breastfeeding with solids. |
| 47LB | POPULATION PHARMACOKINETICS OF TENOFOVIR IN HIV-1-INFECTED PREGNANT WOMEN AND THEIR NEONATES: TEmAA ANRS 12109 Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:88 (abstract no. 47LB) Deborah hirt1, S Urien1, E Rey2, D Ekouevi3, S Blanche4, G gray5, P Coffie3, K Leang Sim6, F Dabis7, and J M Treluyer1 TDF 600 mg before delivery produces similar concentrations to those of HIV infected people taking 300 mg daily. If time elapsed between maternal administration and delivery is >12 hours, 2 tablets of TDF/FTC should be re-administered. Tenofovir was shown to have good placental transfer. Administering 13 mg/kg of TDF as soon as possible after birth should produce neonatal concentrations comparable to those observed in adults. |
| 48 | EFFECTIVENESS OF NNRTI-CONTAINING ART IN WOMEN PREVIOUSLY EXPOSED TO A SINGLE DOSE OF NEVIRAPINE: A MULTI-COUNTRY COHORT STUDY Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:89 (abstract no. 48) Paul Weidle1, J Stringer2, M McConnell1,3, J Kiarie4, T Anekthananon5, T Jariyasethpong6, D Potter2, W Mutsotso7, C Borkowf1, O Bolu1, and The NNRTI Response Study Team A high proportion (79%) of women in this cohort responded to 6 months of NNRTI-based ART, whether previously exposed to single-dose NVP or not. These data do suggest an increased risk of treatment failure among women with recent single-dose NVP exposure, but not with single-dose NVP exposure >12 months before initiation of NNRTI-based ART. Treatment with ART or perinatal HIV prevention strategies other than single-dose NVP should be considered for pregnant women who are likely to initiate ART within 1 year after delivery. |
| Session 15—Symposium Voyages through the Cell: Imaging Viral Traffic |
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| 49 | PRE-INTEGRATION COMPLEX TRANSPORT TO THE NUCLEUS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:89 (abstract no. 49) Nathalie Arhel and P Charneau In the absence of central DNA Flap formation, decapsidation is impaired and linear DNA remains trapped within an integral capsid shell precluding translocation through the nuclear pore. We therefore show that DNA Flap formation, the very last event of HIV-1 reverse transcription, acts as a viral promoting element for the uncoating of HIV-1 at the nuclear pore. |
| 50 | LIVE IMAGING OF CELL-TO-CELL TRANSMISSION OF RETROVIRUSES Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:90 (abstract no. 50) N Sherer, M Lehmann, J Jin, and Walther Mothes Interestingly, recent results in our laboratory indicate that the basic underlying principles of filopodial and synaptic modes of virus transmission are related. Broad synaptic interfaces also feature an interdigitated filopodial network promoting virus transmission along the outer surface. We are next applying our visual approach to the study of HIV transmission from cell to cell. |
| 51 | ELECTRON CRYOTOMOGRAPHY OF HIV VIRIONS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:90 (abstract no. 51) Grant Jensen Tomography of mature particles highlights the diversity of capsid shapes that form and allowed the cone angle of the majority class to be measured directly, confirming the “5/7 fullerene cone” model for its architecture. |
| 52 | ELECTRON TOMOGRAPHY OF IMMUNODEFICIENCY VIRUSES AND STRUCTURAL MECHANISMS OF CELLULAR ENTRY Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:90 (abstract no. 52) Sriram Subramaniam Our studies have led to discovery of the viral “entry claw,” a unique structure formed at the junction between SIV/HIV and T cells, to the structural mechanisms underlying neutralization of HIV and SIV by a potent polyvalent CD4 construct, and to new insights into the structures of surface glycoproteins on SIV and HIV. |
| Session 16—Symposium Curbing the US Epidemic |
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| 53 | WHAT'S DRIVING THE US EPIDEMIC IN MSM Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:90 (abstract no. 53) Ron Stall, M Friedman, M Marshal, and S Wisniewski This presentation will review current HIV incidence data among MSM in the United States to provide estimates of expected prevalence rates of HIV infection among emerging cohorts of young gay men if incidence rates are not lowered. The presentation will also present findings from a qualitative review of ongoing correlates of HIV risk-taking and HIV incidence among MSM in the United States to show what new areas of prevention efficacy need to be tapped if we are to lower HIV infection rates among MSM. The qualitative review will focus on: the need for greater information regarding the precise risks of HIV transmission for very specific sexual practices among men; enhancing a sense of responsibility for sexual safety; enhancing self-knowledge regarding sexual risk; dealing with racism and cultural differences; addressing multiple epidemics that drive sexual risk; creating strategies to reduce community viral loads; and finding ways to translate program efficacy into effectiveness. The presentation will culminate with an argument for a “prevention cocktail” approach to lower HIV incidence rates, in which multiple mechanisms of prevention action can be marshaled in tandem to enhance health among MSM in the United States. |
| 54 | WHAT'S DRIVING THE US EPIDEMIC AMONG WOMEN Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:91 (abstract no. 54) Adaora Adimora Slowing the HIV epidemic among minority women will require addressing not only individual-level behavioral factors, but also the distal societal determinants that support and maintain HIV transmission. |
| 55 | PREVENTION FOR POSITIVES Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:91 (abstract no. 55) Simon Rosser Whether the United States can effectively prevent the next phase of the epidemic without universal health care is argued. |
| 56 | ADDRESSING SUBSTANCE ABUSE Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:91 (abstract no. 56) David Vlahov The successful introduction of buprenorphine has expanded the availability of opioid treatment and has been shown to be effective in HIV risk reduction and appropriate for those abusing prescription analgesics. While pharmacological advances for stimulant abuse have been limited, there is evidence suggesting benefits of behavioral therapies. For occasional users, brief, office-based, and other low-threshold interventions have demonstrated efficacy, whereas more extensive approaches—such as cognitive behavioral therapy, motivational interviewing, and contingency management—have been successful for dependent users. Research on mechanisms of how drugs influence sex risk will contribute to shaping the content of interventions. Moving forward, research and practice need to better embrace authentic multi-disciplinary perspectives that include greater emphasis on substance abuse issues. |
| Session 17—Oral Abstracts Hepatitis Co-infection |
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| 57 | HIV ENTRY AND REPLICATION IN STELLATE CELLS PROMOTES CELLULAR ACTIVATION AND FIBROGENESIS: IMPLICATIONS FOR HEPATIC FIBROSIS IN HIV/HCV CO-INFECTION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:91 (abstract no. 57) Ana Tuyama, F Hong, A Mosoian, P Chen, B Chen, I Fiel, A Schecter, M Klotman, and M Bansal HIV enters and actively replicates within HSC independent of CD4. Both viral entry as well as exposure of cells to viral envelope glycoproteins can promote activation and collagen induction in HSC. These results suggest that direct infection or Env-mediated activation of HSC may contribute to rapid development of fibrosis in patients co-infected with HIV/HCV. |
| 58 | HIV-RELATED MICROBIAL TRANSLOCATION, A MECHANISM FOR LIVER DISEASE Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:92 (abstract no. 58) A Balagopal1, F Philp1, J Astemborski1, T Block2, A Mehta2, G Kirk1, S Mehta1, A Cox1, S Ray1, and David Thomas1 Markers of microbial translocation are strongly associated with both HCV-related cirrhosis and HIV infection suggesting immune activation may be a common pathogenic mechanism. |
| 59 | SUSTAINED LONG-TERM ANTIVIRAL MAINTENANCE WITH PEGYLATED INTERFERON IN HCV/HIV-CO-INFECTED PATIENTS: EARLY VIRAL RESPONSE AND EFFECT ON FIBROSIS IN TREATED AND CONTROL SUBJECTS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:92 (abstract no. 59) Kenneth Sherman1, J Andersen2, A Butt3, Z Goodman4, T Umbleja2, B Alston6, M Koziel5, M Peters7, M Sulkowski8, R Chung9, and ACTG A5178 Study Team Pegylated interferon/weight-based ribavirin achieved higher levels of early virologic response than observed in ACTG 5071 which used lower doses of ribavirin (55.6% vs. 41%). Race appears to be an important independent factor in early virologic response. In contrast to recent reports, this randomized controlled trial failed to identify significant change in hepatic fibrosis among untreated non-early virologic responses over 72 weeks. |
| 60 | SUSTAINED VIROLOGICAL RESPONSE TO INTERFERON PLUS RIBAVIRIN REDUCES LIVER-RELATED COMPLICATIONS AND MORTALITY IN HIV/HCV-CO-INFECTED PATIENTS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:92 (abstract no. 60) Juan Berenguer1, J Alvarez-Pellicer2, J Lopez Aldeguer3, M Von-Wichman4, C Quereda5, J Mallolas6, J Sanz7, C Tural8, J Bellon1, J Gonzalez2, and The GESIDA 3603 Study Group Conclusions: Our results suggest that the achievement of an SVR after IFN-RBV therapy in HIV/HCV+ patients reduces liver-related complications and mortality. |
| 61LB | HEPATITIS C VIREMIA FOLLOWING SUSTAINED VIROLOGICAL RESPONSE TO PEGYLATED INTERFERON AND RIBAVARIN IN HIV+ MEN WHO HAVE SEX WITH MEN–RE-INFECTION OR LATE RELAPSE? Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:93 (abstract no. 61LB) Rachael Jones1, D Brown2, M Nelson1, S Bhagani2, M Atkins1, M Danta3, G Dusheiko2, O Pybus4, and D Asboe1 Of 8 individuals, 6 who had further HC viremia following SVR, were re-infected with a different HCV strain. Re-infections were likely related to ongoing high-risk sexual activity. The clustering seen indicates that this is a relatively closed population, exchanging HCV within the cohort. In 2 cases, the strains were closely related indicating either late relapse or possibly re-infection from a common source. |
| 62 | 3 INTERLINKED MECHANISMS OF INHIBITION OF HIV-1 REVERSE TRANSCRIPTASE BY THE HBV DRUG ENTECAVIR Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:93 (abstract no. 62) Egor Tchesnokov1, A Obikhod2, R Schinazi2, and M Gotte1 The results of this study delineate 3 interlinked mechanisms of inhibition of HIV-1 RT by ETV. DNA synthesis is compromised at positions n+1 and n+4, and, during synthesis of the second DNA strand, at position n+1. The combined data provide a rational for mechanism-based approaches in the development of more potent non-obligate chain-terminators. |
| 63 | THE ANTI-HIV ACTIVITY OF ENTECAVIR: SERUM HIV RNA DECREASES AND SELECTION OF THE M184V MUTATION OCCURS IN BOTH ART-NAÏVE AND -EXPERIENCED HIV/HBV-CO-INFECTED INDIVIDUALS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:93 (abstract no. 63) Jennifer Audsley1,2,3, J Sasadeusz1,3, A Mijch1,2, R Baden4, J Caro4,5, H Hunter6, G Matthews7, S Olender8, S Lewin1,2,3, and C Thio9 ETV monotherapy results in a clinically significant reduction in HIV RNA in the majority but not all HIV/HBV-co-infected individuals and can select for the M184V mutation, even in HIV treatment naïve individuals. HIV/HBV-co-infected individuals should not receive ETV monotherapy. |
| 64 | MELD IS THE BEST PREDICTOR OF PRE-TRANSPLANT MORTALITY IN HIV-INFECTED LIVER TRANSPLANT CANDIDATES Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:94 (abstract no. 64) Aruna Subramanian1, M Sulkowski1, B Barin2, D Stablein2, M Curry3, N Nissen4, L Dove5, M Roland6, P Stock7, and M Ragni8 HIV+ liver transplant candidates have similar pre-transplant mortality characteristics as HIV– controls. While lower CD4 counts and detectable HIV RNA are associated with death, baseline MELD appears to be the only significant predictor of pre-transplant mortality in HIV-infected liver transplant candidates. |
| Session 18—Plenary Challenges in Pediatric and Adolescent HIV Care |
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| 65 | CHALLENGES IN PEDIATRIC AND ADOLESCENT HIV CARE Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:94 (abstract no. 65) Lynne Mofenson In resource-rich countries, enhanced survival of HIV-infected children has resulted in new challenges, including management of HIV in adolescents, complications of therapy, and transition to adult care. In resource-limited countries, challenges include early infant diagnosis, development of pediatric drug formulations, and optimal treatment of infants exposed to maternal prophylaxis regimens. |
| Session 19—Plenary Natural Enhancers and Inhibitors of HIV Infection |
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| 66 | NATURAL ENHANCERS AND INHIBITORS OF HIV INFECTION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:95 (abstract no. 66) J Munch1, L Standker2,3, W G Forssmann2,3, and Frank Kirchhoff1 Our ongoing experiments aim to further elucidate the enhancing mechanism and to identify agents that suppress this effect. Moreover, we are investigating the effect of seminal fluid and different fibrils on infection by other viruses to clarify whether amyloid-like aggregates may play a more general role in the spread of sexually transmitted diseases. |
| Session 20—Oral Abstracts Insights into Neuropathogenesis |
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| 67 | REDUCING THE PREVALENCE OF PRIMARY HIV BRAIN PATHOLOGY BY ANTIRETROVIRALS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:95 (abstract no. 67) Ian Everall1, F Vada1, S Letendre1, D Lazzaretto1, B Gelman2, S Morgello3, E Singer4, R Ellis1, E Masliah1, I Grant1, and National NeuroAIDS Tissue Consortium and the UCSD HIV Neurobehavioral research Center This is the first large-scale brain autopsy study to assess the potential influence of class of ARV exposure in relation to the risk for developing HBP. Individuals who were untreated prior to death or who were taking a PI-NRTI regimen had similar prevalences of HBP. However, the risk was halved when the regimen included an NNRTI. Neuroprotection was also signified by lower plasma viral load and better estimated ARV penetration. |
| 68 | LOW-GRADE IMMUNE RESTORATION DISEASE MAY LIMIT RECOVERY FROM HIV-ASSOCIATED NEUROCOGNITIVE IMPAIRMENT Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:96 (abstract no.68) Scott Letendre, R Ellis, L Cysique, M Cherner, S Gibson, R Heaton, A McCutchan, and The HNRC Group In this carefully controlled study, a majority of participants with HNCI did not normalize their neuropsychological performance after 24 weeks of ART. Those who had less improvement had lower CD4+ nadirs and higher HIV RNA levels in CSF before ART and greater expansion of CD8+ cells in blood during ART. These findings suggest that greater expansion of CD8+ cells in response to ART may limit recovery from HNCI, possibly via homing of subsets of CD8+ cells, such as effector memory T cells, to the brain. |
| 69 | ELEVATED PLASMA ENDOTOXIN ASSOCIATED WITH MONOCYTE ACTIVATION AND REDUCED BDNF IN AIDS PATIENTS WITH DEMENTIA Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:96 (abstract no. 69) Petronela Ancuta1, K Kunstman2, E Y Kim2, P Autissier3, M Mefford4, D Stone5, S Wolinsky2, and D Gabuzda4 These results suggest a role for elevated LPS levels in driving monocyte expansion and activation in chronic HIV infection, thereby contributing to the pathogenesis of HAD, and provide evidence that cofactors linked to substance abuse may influence these processes. Reduced circulating BDNF levels, possibly a consequence of sustained monocyte activation and LPS tolerance, may be a factor that contributes to neurocognitive impairment in HIV/AIDS. |
| 70 | HIV INFECTION OF THE CEREBROSPINAL FLUID OF ELITE CONTROLLERS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:96 (abstract no. 70) John Probasco, S Deeks, E Lee, R Hoh, T Liegler, R Price, and S Spudich CSF HIV infection in elite controller subjects is evident at the lower limits of HIV RNA viral load detection. The character of CSF HIV infection and the degree of immunoactivation in these individuals is similar to that of HIV– and HIV+ subjects treated to plasma viral loads <50 RNA copies/mL, yet distinct from that of neuroasymptomatic untreated HIV+ subjects. |
| 71 | INFLUENCE OF IMMUNOLOGICAL, VIROLOGICAL, AND RADIOLOGICAL DETERMINANTS IN THE CLINICAL OUTCOME OF PATIENTS WITH PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:97 (abstract no.71) A Marzocchetti1, T Tompkins1, D Clifford2, R Gandhi3, S Kesai4, J Berger5, D Simpson6, A DeLuca7, and Igor Koralnik8 JCV detection in plasma is significantly more frequent in PML than HIV+ patients. The association between JCV-specific CTL and better survival was observed in HIV+PML only, where it was a highly significant predictor. Conversely, HIV+PML patients with baseline CD4 counts <200 had a worse survival than those with higher CD4 counts. Despite the association of clinical features with JCV-specific CTL (contrast enhancement, IRIS), those cannot be considered as surrogate for the prognostic value of the CTL. |
| 72 | NATURAL GENETIC RESISTANCE TO LENTIVIRAL CNS DISEASE: A NEUROPROTECTIVE MHC CLASS I ALLELE IN SIV-INFECTED MACAQUES Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:97 (abstract no. 72) Joseph Mankowski1, S Queen1, C Fernandez2, P Tarwater3, J Karper1, R Adams1, and S Kent2 The concordant findings of decreased incidence of SIV encephalitis, lower macrophage activation, markedly reduced CNS viral load, and decreased amyloid precursor protein (APP) accumulation in macaques expressing the Mane-A*10 allele strongly suggest that particular MHC class I alleles play major neuroprotective roles in lentiviral-induced CNS disease. |
| Session 21—Oral Abstracts HIV in Women and Children |
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| 73 | ALTERNATIVES TO PROLONGED BREASTFEEDING AND INCIDENCE OF PREGNANCIES AMONG HIV-INFECTED WOMEN: THE ANRS 1201-1202 DITRAME PLUS COHORT IN ABIDJAN, CÔTE D'IVOIRE, 2001 TO 2005 Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:98 (abstract no. 73) I Viho1, R Becquet2,3, D Ekouevi1,2, H Brou1, A Yao1, F Dabis2,3, C Amani-Bosse1, A Desgree-du-Lou4, M Timite-Konan5, Valeriane Leroy2,3, and ANRS 1201-1202 DITRAME PLUS Study Group Replacement feeding is not responsible of a greater incidence of pregnancy in this urban West African population. Our results highlight the public health importance to deliver appropriate family planning services for HIV-infected women. |
| 74 | INCIDENCE AND DETERMINANTS OF PREGNANCY AMONG WOMEN RECEIVING ART IN RURAL UGANDA Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:98 (abstract no. 74) Jaco Homsy1,2, R Bunnell2, D Moore2,3, R King2, S Malamba2, R Nakityo2, D Glidden1, C Likicho2, J Tappero2, and J Mermin2 In this cohort, pregnancy incidence increased with time on ART. Most pregnancies were unintended and very few women were using semi-permanent or permanent family planning methods. Patients on ART should be routinely counseled on the effects of ART in restoring health and fertility, and comprehensive family-planning services should be integrated into ART services with an emphasis on using dual methods. |
| 75 | IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME IN HIV-INFECTED INFANTS AND YOUNG CHILDREN INITIATING ART Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:99 (abstract no. 75) Kelly Smith1, L Kuhn2, A Coovadia3, T Meyers4, B Marais3, G Barry3, and E Abrams2 IRIS, particularly BCG-related disease, was common in this cohort of young children initiating HAART. Children starting ART at a young age with low CD4 may be particularly vulnerable. The effect of IRIS on HAART treatment outcomes requires further study. |
| 76 | Clinical and Immunological Characteristics of Very Young Infants with HIV Infection: Children with HIV Early Antiretroviral Study Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:99 (abstract no. 76) Heather Jaspan1, L Myer2, A Violari3, S Madhi4, J Steyn3, R van Niekerk3, W Stevens3, and M Cotton1 This is the one of the first clinical descriptions of a large cohort of very young HIV-infected and exposed infants from South Africa. When evaluating children at risk for HIV whose status is unknown, the lack of certain findings may be useful for identifying those who are less likely to be HIV infected when HIV polymerase chain reaction (PCR) is not possible, and in identifying those without severe immunosuppression when CD4 percentage is not available. |
| 77LB | RANDOMIZED, CONTROLLED TRIAL OF 3 APPROACHES TO MANAGEMENT OF HIV-INFECTED INFANTS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:99 (abstract no. 77LB) Andrew Prendergast1, F Chonco2, G Tudor-Williams3, W Mphatswe2, A Cengimbo2, C Thobakgale2, K Dong4, H Coovadia2, B Walker4, and P Goulder1 Structured treatment interruptions in acute infant HIV infection did not improve virologic control and increased regimen switches. However, continuous ART from birth, stopped at 12 months, provides a promising novel treatment strategy in infants. Immediate ART prevents the rapid disease progression that characterizes HIV in infancy and enables immune reconstitution. Stopping ART at 1 year reduces cost, toxicity, and drug resistance. Time off therapy is predictable from CD4 percentage at birth, enabling identification of eligible infants at diagnosis. |
| 78LB | SAFETY AND EFFICACY OF DARUNAVIR CO-ADMINISTERED WITH LOW-DOSE RITONAVIR IN TREATMENT-EXPERIENCED CHILDREN AND ADOLESCENTS AT WEEK 24 Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:100 (abstract no. 78) R Bologna1, S Rugina2, P Cahn3, P Flynn4, S Blanche5, B Van Baelen6, R De Greef6, L Lavreys6, T Van De Casteele6, and Sabrina Spinosa-Guzman6 DRV/r was an effective treatment in treatment-experienced HIV-1-infected pediatric patients (6 to 17 years) due to the favorable tolerability and pharmacokinetics profiles, and virologic response rates at Week 24. |
| Session 22—Oral Abstracts New Mechanisms of Resistance and Virologic Failure |
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| 79 | MECHANISM BY WHICH N348I IN HIV-1 REVERSE TRANSCRIPTASE CONFERS DUAL ZIDOVUDINE/NEVIRAPINE RESISTANCE Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:100 (abstract no. 79) Soo-Huey Yap1,2, J Radzio3,4, N Sluis-Cremer3, and G Tachedjian1,5 This study defines the mechanism by which N348I confers dual AZT/NVP resistance and explains why this mutation may be selected in response to therapies containing these drugs. Furthermore, it expands our knowledge of how mutations, distal from the polymerase active site and NNRTI-binding pocket, can confer drug resistance. |
| 80 | MOLECULAR MECHANISMS FOR 3’-AZIDO-3’-DIDEOXYTHYMIDINE-RESISTANCE CONFERRED BY MUTATIONS IN THE CONNECTION AND RNASE H DOMAINS OF HIV-1 REVERSE TRANSCRIPTASE Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:101 (abstract no. 80) Jessica Brehm, N Sluis-Cremer, and J Mellors Q509L and A371V/Q509L with TAM impair formation of RNase H cleavage products, which increases AZT-MP excision on RNA/DNA duplexes by reducing template degradation. In addition, Q509L and A371V/Q509L increase the efficiency of excision on short RNA/DNA duplexes. A371V with TAM had little effect on AZT-MP excision or RNase H cleavage, thus its role remains undefined. |
| 81 | CONNECTION DOMAIN MUTATIONS N348I AND A360V IN HIV-1 RT SELECTIVELY FACILITATE EXCISION OF AZT BY IMPROVING ACCESS TO TRANSIENTLY FORMED RNA/DNA HYBRIDS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:101 (abstract no. 81) G Beilhartz, Maryam Ehteshami, B Scarth, E Tchesnokov, and M Gotte Selective dissociation of transiently formed hybrids from RNase H-competent complexes provides a mechanism for the selective increase in AZT resistance associated with connection mutations N348I and A360V. |
| 82 | CIRCUMVENTING DRUG RESISTANCE: USING THE SUBSTRATE ENVELOPE HYPOTHESIS TO DEVELOP ROBUST NOVEL HIV-1 PROTEASE INHIBITORS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:101 (abstract no. 82) M Nalam1, A Ali1, K Reddy1, M Altman2, S Chellappan3, S Anjum1, T Rana1, M Gilson3, B Tidor2, and Celia Schiffer1 This design effort of novel HIV-1 protease inhibitor validates the substrate envelope hypothesis that it is possible to avoid susceptibility to drug resistant variants by designing inhibitors to fit within the substrate recognition region of the active site. These results outline a new paradigm for developing new robust inhibitors that are less susceptible to resistant variants against quickly evolving therapeutic targets. |
| 83 | PRESENCE OF MINOR POPULATIONS OF Y181C MUTANTS DETECTED BY ALLELE-SPECIFIC PCR AND RISK OF EFAVIRENZ FAILURE IN TREATMENT-NAÏVE PATIENTS: RESULTS OF AN ACTG 5095 CASE-COHORT STUDY Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:102 (abstract no. 83) Roger Paredes1,2, C Lalama3, H Ribaudo3, B Schackman4, C Shikuma5, W Meyer, III6, F Giguel1, K Squires7, R Gulick4, and D Kuritzkes1 In antiretroviral-naïve subjects without evidence of NNRTI resistance by bulk sequencing, presence of minority Y181C mutants detected by ASPCR more than tripled the risk of virologic failure of EFV-based regimens. |
| 84LB | EMERGENCE OF HIV-1 DRUG RESISTANCE AMONG BREASTFEEDING INFANTS BORN TO HIV-INFECTED MOTHERS TAKING ANTIRETROVIRALS FOR PREVENTION OF MOTHER-TO-CHILD TRANSMISSION OF HIV: THE KISUMU BREASTFEEDING STUDY, KENYA Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:102 (abstract no. 84LB) Clement Zeh1, P Weidle2, L Nafisa1, H Musuluma1, J Okonji1, E Anyango1, P Bondo1, R Masaba1, M Thigpen2, and T Thomas1 Among infants who became HIV-infected by the first 6 weeks of life, ARV resistance was initially not detected suggesting resistant virus may not have been transmitted from the mother. However, resistance emerged during the breastfeeding period, likely due to the transfer of ARV from breast-milk. Differing HIV resistance patterns depending on the mothers’ treatment may have implications for the choice of ARV for mothers during the breastfeeding period and for subsequent treatment of infants who become HIV-infected. |
| Session 23—Oral Abstracts HIV Vaccines |
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| 85 | GEOVAX CLADE B DNA/MVA HIV/AIDS VACCINE IS WELL TOLERATED AND IMMUNOGENIC WHEN ADMINISTERED TO HEALTHY SERONEGATIVE ADULTS (HVTN 065 PART A) Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:103 (abstract no. 85) Harriet Robinson1, P Goepfert2, C Hay3, S Frey4, W Blattner5, P Wright6, M Elizaga7, L Qin7, B Moss8, and HVTN 065 Protocal Team The majority of vaccinated participants demonstrated cellular responses at both low and high doses to this well-tolerated DNA/MVA vaccine regimen. Testing of the vaccines in additional volunteers with 3-injection regimens using a single DNA prime, or MVA-only; and planning for a phase II trial are underway. |
| 86 | CELLULAR IMMUNE RESPONSES IN HIV-1 UNINFECTED ADULT TANZANIAN VOLUNTEERS ENROLLED IN A PHASE I/II MULTICLADE HIV-1 DNA PLASMID VACCINE (VRC-HIVDNA016-00-VP)/ADENOVIRUS-5 VECTOR(VRC-HIVADV014-00-VP) BOOST VACCINE TRIAL Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:103 (abstract no. 86) Alexandra Schuetz1,2, A Haule1, M Schunk1, L Maboko1, M Hoelscher1, M Robb2, N Michael2, B Graham3, J Cox2, and M de Souza2,4 This vaccine regimen induced robust cellular immune responses at multiple time points in the majority of vaccinees. However, recent concerns using rAd5 vectors will require further research to supports its safety in settings with high baseline titers of Ad5 neutralizing antibodies. |
| 87 | THERAPEUTIC VACCINATION WITH A REPLICATION DEFECTIVE ADENOVIRUS TYPE 5 HIV-1 GAG VACCINE IN A PROSPECTIVE, DOUBLE-BLINDED, PLACEBO-CONTROLLED TRIAL (ACTG 5197) Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:104 (abstract no. 87) Robert Schooley1, H Wang2, J Spritzler2, M Lederman3, D Havlir4, D Kuritzkes5, C Battaglia6, C Godfrey7, M Robertson8, B Schock9, and AIDS Clinical Trials Group The Ad5 HIV-1 gag vaccine was generally safe and well tolerated. Although there was a trend in favor of viral suppression among vaccine recipients during an analytical treatment interruption, the differences in HIV-1 RNA levels did not meet protocol-specified levels of significance. |
| 88LB | EFFICACY RESULTS FROM THE STEP STUDY (MERCK V520 PROTOCOL 023/HVTN 502): A PHASE II TEST-OF-CONCEPT TRIAL OF THE MRKAD5 HIV-1 GAG/POL/NEF TRIVALENT VACCINE Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:104 (abstract no. 88LB) M Robertson1, D Mehrotra1, D Fitzgerald2, A Duerr3, D Casimiro1, J McElrath3, D Lawrence4, and Susan Buchbinder5 There was no evidence that the Merck Ad5 trivalent vaccine prevented infection or lowered viral set-point. In multivariate analysis of baseline risk factors, vaccination appeared associated with an increased risk of HIV acquisition in men with pre-existing Ad5 immunity and in uncircumcised men. We are awaiting additional data on herpes simplex virus-2 (HSV-2) status, HLA typing, and sexual network clustering to explore possible confounding factors for HIV acquisition in STEP study volunteers. Because of the implications for the development of other CMI-based vaccines, it will be important to understand the potential mechanisms underlying these results. |
| 89LB | IMMUNOLOGICAL CHARACTERIZATION OF SUBJECTS FROM THE STEP STUDY: A PHASE IIB TEST-OF-CONCEPT TRIAL OF THE MRKAD5 HIV-1 GAG/POL/NEF TRIVALENT VACCINE Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:104 (abstract no. 89LB) Michael Robertson1, D Casimiro1, S De Rosa2, S Dubey1, L Kierstead1, and J McElrath2 Laboratory investigations are underway to gain insight into immunological factors that may explain in part the clinical outcomes of the STEP trial. From data thus far, no obvious immune profile distinguishes the cases from non-cases or appears to explain the greater infection rates in vaccinees with prior Ad5 immunity. Results from future laboratory investigations, in progress and planned, of responses to the trans-gene and vector itself, as well as analysis of immune activation in blood and mucosally, will have important implications on the directions of other T cell-based vaccine development and the HIV vaccine field in general. |
| Session 24—Plenary Scientific Obstacles to an Effective HIV Vaccine |
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| 91 | SCIENTIFIC OBSTACLES TO AN EFFECTIVE HIV VACCINE Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:105 (abstract no. 91) Ronald Desrosiers These obstacles will be summarized, and a series of questions will be posed and addressed: Is an effective HIV-1 vaccine feasible at the current time? Should we be surprised by the failure of the Merck recombinant adenovirus product to demonstrate efficacy? Do any of the products currently in the pipeline hold any reasonable promise for efficacy? Is there potential for negative ramifications following repeated efficacy trial failures? Do we have the right balance of discovery research versus product development, product manufacturing and clinical testing? |
| Session 25—Plenary AIDS Vaccine at the Crossroads |
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| 92 | AIDS VACCINE AT THE CROSSROADS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:105 (abstract no. 92) Neal Nathanson I will comment on several issues relevant to this discussion, including: What lessons is nature trying to teach us? Among the vast body of knowledge about HIV and AIDS, are there some important clues as to promising leads? How do we wrest the truth from our nonhuman primate co-workers? Although some have concluded that challenge studies with nonhuman primates misled the field, is it more logical to use the STEP trial to better calibrate monkey models to evaluate candidate immunogens? In view of the general consensus that broadly reactive neutralizing antibody is the potential key to an effective AIDS vaccine, are there alternative approaches that might help to cut this Gordian knot? If we can’t prevent or eliminate HIV infection, can we live with it? Could a vaccine that fails to prevent HIV infection sufficiently modulate the very early events to convert HIV into a chronic disease that is not necessarily fatal? Absent a vaccine, can the HIV/AIDS epidemic be controlled effectively, particularly in high prevalence settings? Is it time for another Levine report? Do we need a full-scale evaluation of the direction of AIDS vaccine research? |
| Session 30—Symposium The Emerging Science of HIV Prevention in Women |
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| 93 | MICROBICIDES: RAPID EVOLUTION SINCE 2000 Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:105 (abstract no. 93) Quarraisha Abdool Karim This has enabled the expansion of product formulation and delivery from topical gels in individual, pre-filled applicators to oral and long-acting injectable formulations, physical barriers, slow-release vaginal rings, and potentially implants— all reminiscent of developments in hormonal contraceptive options. While the major beneficiaries of an efficacious microbicide will remain women, the more recent increase in trials that assess safety during rectal use may provide an additional option for women engaging in anal sex and men who have sex with men. With clinical trial results on HIV protection for several products becoming available over the next 24 to 30 months, demonstration of at least partial effectiveness will provide the needed thrust to validate animal models, including new animal models, such as BLT humanized mice. Upon proof of concept, the next microbicide frontier will likely be the development of combination products that target various points of viral entry in the genital tract, antiretroviral combinations and/or more specific anti-HIV co-receptor blockers. |
| 94 | IMPACT OF HORMONAL CONTRACEPTION ON HIV ACQUISITION, CERVICO-VAGINAL VIRAL SHEDDING, AND DISEASE PROGRESSION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:106 (abstract no. 94) Elizabeth Stringer Data from these studies, as well as a large multi-country HIV treatment cohort, will be reviewed. |
| 95 | GENITAL COMPARTMENTALIZATION OF ORALLY AND TOPICALLY ADMINISTERED ANTIRETROVIRALS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:106 (abstract no. 95) Angela Kashuba Understanding pharmacologic compartmentalization can inform clinical trials for optimal selection of drug, dose, and dosing frequency, and to provide biologic plausibility to the interpretation of such trials. In this presentation, current fluid, tissue, and cellular drug exposure data available for animals and humans in the settings of PrEP, PEP, and treatment of the index case will be reviewed, in addition to the challenges investigators face in generating such data. |
| 96 | VAGINAL FLORA, CO-INFECTIONS AND IMMUNE CELLS IN THE GENITAL MUCOSA: IMPLICATIONS FOR HIV TRANSMISSION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:106 (abstract no. 96) Rupert Kaul We conclude that a variety of genital co-infections appears to enhance HIV susceptibility (and secondary transmission), and a common pathway for this effect—as well as for potential increases in HIV susceptibility associated with candidate vaginal microbicides—may be the local recruitment of activated mucosal immune cells. HSV-2 infection and alterations in vaginal flora, due to their high population prevalence and chronic persistence, may be particularly important drivers of HIV transmission. |
| Session 31—Oral Abstracts HIV Molecular Biology and Host Cell Interactions |
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| 97 | EARLY INTERACTIONS OF FLUORESCENTLY LABELED HIV WITH THE FEMALE GENITAL TRACT Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:106 (abstract no. 97) Scott McCoombe1, A Trull1, M McRaven1, N Byers1, M Anderson1, J Kowalski1, M Dinh1, R Veazey2, and T Hope1 It has been previously suggested that the intact squamous epithelium of the genital mucosa provides a robust barrier against HIV transmission. Studies showing that thinning the vaginal epithelium increases HIV transmission and the inability of cervical diaphragms to protect suggest otherwise. Our findings that HIV can penetrate the intact squamous epithelium of the vagina and ectocervix, gaining access to underlying target cells, suggests that these mucosal tissues play a significantly greater role in HIV transmission than previously thought. |
| 98 | IDENTIFICATION OF LEDGF/p75 PWWP DOMAIN AMINO ACIDS RESIDUES CRITICAL FOR CHROMATIN BINDING AND HIV-1 INFECTION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:107 (abstract no. 98) Michelle Shun, F Di Nunzio, and A Engelman Genetic null cells afford the investigation of LEDGF/p75 function in HIV-1 infection and integration in the absence of competing endogenous protein. Our analyses have revealed PWWP domain residues essential for chromatin binding and HIV-1 infection. |
| 99 | HOST-SPECIFIC ADAPTATION OF THE HIV-1/SIVCPZ GAG MATRIX PROTEIN Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:107 (abstract no. 99) Frederic Bibollet-Ruche1, J Decker1, J Easlick1, B Keele1, Y Li1, J Takehisa1, M Krauss1, G Shaw1, P Sharp2, and B Hahn1 These results identify Gag-30 in the SIVcpz matrix protein as a target of strong host-specific selection. Although the specific function of this residue remains to be determined, it is clear that adaptive changes at this site were required for efficient replication of SIVcpz following transmission to the human host. |
| 100 | Vpr BINDS TO DCAF1 AND TO DDB1 TO MEDIATE ITS BIOLOGICAL FUNCTIONS IN A SPECIES-SPECIFIC INTERACTION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:107 (abstract no. 100) Yoshiyuki Hakata and N Landau Vpr binds to DDB1 and DCAF1 to form a trimeric complex. The binding sites on Vpr for the 2 host proteins can be separated genetically, and binding to both proteins is required for function. The species-specificity of the interaction provides further confirmation for the biological significance for the interaction of Vpr with DDB1 and DCAF1. |
| 101 | THE ROLE OF HUMAN STAUFEN IN THE INTRACELLULAR TRAFFICKING OF UNSPLICED HIV-1 RNA Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:108 (abstract no. 101) Nan Yan1,2 and J Lieberman1,2 Results presented here suggest a possible mechanism for unspliced HIV-1 RNA trafficking to the plasma membrane that involves hStau and microtubule. |
| 102 | IDENTIFICATION OF A NOVEL ESCRT-I SUBUNIT AND OTHER ESCRT-I BINDING FACTORS REQUIRED FOR EFFICIENT HIV-1 RELEASE Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:108 (abstract no. 102) E Morita1, Virginie Sandrin1, M A Karren1, S Gygi2, S Morham3, and W Sundquist1 Several of these proteins have now been functionally implicated in HIV release and infectivity, and their phenotypes and mechanisms of action are currently under investigation. |
| 103 | ROLE OF GGA AND ARF PROTEINS IN HIV-1 ASSEMBLY AND RELEASE Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:108 (abstract no. 103) A Joshi1, J Bonifacino2, and Eric Freed1 These findings identify the GGA proteins as novel modulators of HIV-1 release, and the Arf proteins as critical cellular cofactors in retroviral Gag trafficking to the plasma membrane. |
| 104a | MODULATION OF VIRAL ASSEMBLY AND VIRION RELEASE BY Vpu Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:109 (abstract no. 104a) John Guatelli1,2, D Goff1, and N Van Damme2 The Vpu-related virion-release defect is associated with the accumulation of Env and proteolytically processed Gag in late endosomes. These endosomes also contain the cellular protein BST-2/CD317. This protein fulfills criteria as a Vpu-modulated factor that restricts virion-release: BST-2/CD317 is expressed constitutively in specific cell lines; it is induced by interferon; and Vpu decreases its expression. The unusual structure of BST-2/CD317, which includes a transmembrane domain and a GPI-modification, provides a potential mechanism by which this protein could tether lipid raft-enriched nascent virions to cellular membranes. |
| 104bLB | IDENTIFICATION OF HOST PROTEINS REQUIRED FOR HIV INFECTION THROUGH A FUNCTIONAL GENOMIC SCREEN Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:109 (abstract no. 104bLB) Abraham Brass1,2,3, D Dykxhoorn3,4, Y Benita3, N Yan3,4, A Engelman5, R Xavier3, J Lieberman3,4, and S Elledge2,3 This effort begins to illustrate the power with which RNA interference and forward genetics can be used to expose the dependencies of human pathogens such as HIV, and in so doing identify potential targets for therapy. |
| Session 32—Symposium Aging and AIDS |
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| 105 | IMMUNE EXHAUSTION IN AGING AND AIDS: PARALLEL MECHANISMS AND POSSIBLE SOLUTIONS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:110 (abstract no. 105) Rita Effros These telomerase-based approaches, and others involving maintenance of CD28 expression, may lead to practical therapeutic strategies for preventing immune exhaustion in both young and progressively increasing population of older HIV-infected persons. |
| 106 | THE EFFECT OF AGING ON HUMAN PHARMACOLOGY Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:110 (abstract no. 106) Charles Flexner In this example, older subjects reported better adherence than younger subjects. After adjustments for adherence, age was negatively associated with LPV clearance rate, consistent with an age-related loss of CYP 3A4 activity. |
| 107 | CONTRIBUTIONS OF AGE-RELATED MORBIDITIES Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:110 (abstract no. 107) William Powderly Management of older persons with HIV should include baseline evaluation of cardiovascular risk and regular monitoring of fasting lipid and glucose levels, renal function, and markers of bone disease. Furthermore, because avoidance of metabolic and other toxicities or drug–drug interactions is a key issue, co-morbidities have an important influence on antiretroviral selection. |
| 108 | EPIDEMIOLOGY OF HIV, INCLUDING RESPONSE TO ART, IN OLDER POPULATIONS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:111 (abstract no. 108) Bruno Ledergerber HIV screening should be scaled-up because older individuals are more likely to present for testing and care with lower CD4 cell counts and at more advanced stages of HIV infection than younger individuals. Multiple studies have shown that virological response to ART is better in all older age groups. In patients around 50 this also translates into a better immunologic recovery. With older age, however, CD4 cell count increases tend to weaken. Naturally, all-cause mortality is strongly associated with older age. Country- and gender-adjusted mortality ratios for HIV patients decrease towards one with older age as non-HIV mortality accounts for an increasingly larger proportion in the total mortality experienced. |
| Session 33—Symposium Targeting TB: New Opportunities and Challenges |
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| 109 | HOW CAN SCIENTIFIC ADVANCES CONTRIBUTE TO TB CONTROL Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:111 (abstract no. 109) William Bishai The progress in basic science offers routes for innovation in the fields of diagnostics, therapeutics, and vaccine development for tuberculosis. |
| 110 | PROSPECTS FOR NEW DRUGS FOR TB Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:111 (abstract no. 110) Timothy Sterling Data on the safety and effectiveness of these medications in combination with standard therapy will be discussed as available. An update on studies of short-course treatment of latent TB infection will be provided. Drug interactions between these new anti-TB agents and current ART will also be discussed. |
| 111 | CONCURRENT MANAGEMENT OF TB AND HIV Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:111 (abstract no. 111) Stephen Lawn Despite the challenges inherent in concurrent administration of TB treatment and ART, good treatment outcomes are nevertheless achievable. Increasing evidence shows that standard-dose NNRTI-based regimens can be effectively used with rifampicin-containing TB treatment with excellent virological outcomes. TB immune reconstitution disease presents a clinical challenge, but, so far, data suggest that it is not associated with a high-excess mortality and that it does not have a major effect on overall outcomes in ART programs. A major remaining therapeutic challenge is presented by the difficulties of combining TB treatment with second-line PI-containing ART regimens, especially where rifabutin is not available as an alternative to rifampicin. Much remains to be learned about combining treatment for drug-resistant TB with ART. |
| 112 | CONFRONTING THE CATASTROPHE OF M/XDR TB Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:112 (abstract no. 112) Gerald Friedland and TF CARES Controlling MDR and XDR TB in this context, requires more complete definition of epidemiology and transmission patterns, increased laboratory capacity for culture and drug-susceptibility testing and the rapid implementation of epidemic control measures that reduce aerosolization of and exposure to resistant organisms, particularly among those with HIV co-infection. |
| Session 34—Plenary Advances in the Management of Treatment-experienced Patients: A 2nd Wave of HAART |
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| 113 | ADVANCES IN THE MANAGEMENT OF TREATMENT-EXPERIENCED PATIENTS: A 2nd WAVE OF HAART Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:112 (abstract no. 113) Sharon Walmsley In this session, the newer agents will be discussed in light of their activity in the multi-drug-experienced patient and how to use them to achieve the new goal of complete and durable viral suppression for patients with all levels of drug experience. |
| Session 35—Plenary New Insights into Retrovirus-Host-cell Interactions |
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| 114 | NEW INSIGHTS INTO RETROVIRUS-HOST CELL INTERACTIONS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:112 (abstract no. 114) Paul Bieniasz Several lines of evidence indicate that the antiviral activity consists of protein-based tethers, which we term “tetherins” that cause retention of fully formed retrovirus particles on infected cell surfaces. Using deductive constraints and gene expression analyses, we have identified tetherin as a membrane protein of heretofore unknown function. The observation that tetherin inhibits divergent retroviruses and is widely expressed in the presence of interferon-a raises the possibility that tetherin might be an important component of the broad innate IFN-α-induced antiviral defense against enveloped viruses. Future work will determine the spectrum of viruses against which tetherin is active, precisely how tetherin induces virion retention, and how its action is antagonized by the HIV-1 Vpu protein. |
| Session 36—Oral Abstracts New Insights into Mechanisms of Viral Pathogenecity |
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| 115 | PREFERENTIAL LOSS OF TH17 CD4 T CELLS IN THE GASTROINTESTINAL TRACT OF HIV-INFECTED INDIVIDUALS BUT NOT SIV-INFECTED SOOTY MANGABEYS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:113 (abstract no. 115) Barbara Cervasi1, J Brenchley2, M Paiardini1, S Gordon1, A Asher2, I Frank1, J Else3, D Douek2, and G Silvestri1 The preferential loss of Th17 in the the gastrointestinal tract of HIV-infected individuals represents a new mechanism of mucosal immune dysfunction during HIV infection. These data thus further elucidate the immunodeficiency of HIV disease and may provide a mechanistic basis for the enteropathy and associated microbial translocation that characterize HIV infection. Conversely, maintenance of gastrointestinal Th17 cells may account for the non-progressive nature of non-pathogenic SIV infection in sooty mangabeys. |
| 116 | PREFERENTIAL LOSS OF TH17 T CELLS AT MUCOSAL SITES PREDICTS AIDS PROGRESSION IN SIMIAN IMMUNODEFICIENCY VIRUS-INFECTED MACAQUES Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:113 (abstract no. 116) Valentina Cecchinato1, C Trindade1, J M Heraud1, A Laurence2, J Brenchley3, E Tryniszewska1,4, D Venzon1, D Douek3, J O'Shea2, and G Franchini1 Because Th17 cells play a central role in innate and adaptive immune response to extracellular bacteria, these data provide a rational explanation for the chronic enteropathy in HIV infection. Thus, therapeutic approaches to reconstitute Th17 numbers and/or function may be of benefit in HIV infection. |
| 117LB | PRIMARY SIV INFECTION CAUSES RAPID LOSS OF THE BALANCE BETWEEN TH17 AND T REGULATORY CELL POPULATIONS IN PATHOGENIC INFECTION OF NON-HUMAN PRIMATES Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:113 (abstract no. 117LB) David Favre1, S Lederer2, B Kanwar1, Z M Ma3, S Proll2, Z Kasakow1, C Miller3, M Katze2, and J McCune1 These results suggest that balanced representation of both Treg and TH17 cells plays a unique and possibly determinative role in the setting of acute lentiviral infection. Because IL-17 acts to preserve the integrity of the mucosal barrier, thus enhancing host defenses against microbial agents, maintenance of robust TH17 function in mucosal tissue during SIV infection may decrease systemic inflammation and disease progression by preventing the immune activation that would otherwise occur after microbial translocation and spread. |
| 118 | SIVRCM, A UNIQUE CCR2-TROPIC VIRUS, SELECTIVELY DEPLETES MEMORY CD4+ T CELLS IN PIGTAILED MACAQUES DUE TO RAPID CO-RECEPTOR EXPANSION IN VIVO Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:114 (abstract no. 118) Rajeev Gautam, T Gaufin, I Butler, A Gautam, C Monjure, M Barnes, M Pattison, P Marx, I Pandrea, and C Apetrei Our study showed that SIV can rapidly adapt to induce persistent infection in a new host by expanding co-receptor usage upon cross-species transmission. Selective depletion of effector memory CD4+ T cells by a virus that showed characteristic in vitro tropism for macrophages emphasizes the value of in vivo studies for virus characterization. |
| 119 | BACTERIAL DNA ARE MEASURABLE IN PLASMA OF HIV-INFECTED PATIENTS AND ARE DIMINISHED BY ART Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:114 (abstract no. 119) Wei Jiang1, K Haley1, S Sieg1, M Lederman1, A Aasher2, D Douek2, and J Brenchley2 Plasma levels of bacterial DNA are diminished by application of ART, but are not decreased to undetectable levels. Taken together with previous data demonstrating residual immune activation in individuals treated with ART, these data suggest that microbial translocation and its associated systemic immune activation are the result of the damage that occurs to the gastrointestinal tract during the acute phase of infection and not ongoing viral replication per se. |
| 120 | EVIDENCE FOR PERSISTENT VIRAL REPLICATION IN LYMPH NODE AND GALT OF ARV-TREATED PERSONS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:114 (abstract no. 120) Timothy Schacker1, M Stevenson2, J Brenchley3, D Douek3, and A Haase1 Using complementary methods to detect viral replication we find evidence for persistent infection in lymphatic tissues, especially GALT, in patients on suppressive ARV. This offers a potential explanation for failure to reconstitute GALT, and to a lesser extent lymph node, with ARV. |
| 121 | HIV-1 REBOUND DURING ART INTERRUPTION IS ASSOCIATED WITH A PREFERENTIAL DEPLETION OF CD4+ T CELLS FROM THE GASTROINTESTINAL TRACT Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:115 (abstract no. 121) Saurabh Mehandru1,2, M Poles1,3, K Tenner-Racz4, M LaRoche1, K Rodriguez1, T Evering1, D Castor1, A Lloyd1, P Racz4, and M Markowitz1 The gastrointestinal tract is targeted during ART interruption resulting in further depletion of mucosal CD4+ T cells. Perhaps, CCR5 receptor antagonists may be useful adjuncts in this setting to protect CCR5+CD4+ T cells. Additionally, though anecdotal, 1 patient with prolonged viremic suppression had high levels of HIV-specific CD4+ T cells in tissue compared to the peripheral blood. |
| 122 | SYNDECAN-3 IS A DENDRITIC CELL-SPECIFIC ATTACHMENT RECEPTOR FOR HIV-1 Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:115 (abstract no. 122) L De Witte1, M Bobardt2, T Geijtenbeek1, and Philippe Gallay2 We identified syndecan-3 as a major HIV-1 attachment receptor on DC. We demonstrated that HIV-1 exploits both syndecan-3 and DC-SIGN to mediate HIV-1 transmission. Since DC within the L. propria extend their dendritic processes into the lumen of the vagina, our findings suggest that HIV-1 exploits syndecan-3, richly expressed by dendrites, breaching the epithelial surface, to hijack DC. An effective microbicide should thus target both syndecan-3 and DC-SIGN on DC to prevent transmission. By identifying syndecan-3 as a novel DC-specific attachment receptor for HIV-1, this study sheds light on the interplay between HIV-1, DC and T cells. |
| Session 37—Oral Abstracts Epidemiology of HIV Infection and Scale-up of ART in Developing Countries |
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| 123 | DETERMINANTS FOR HIV ACQUISITION AMONG ADULTS IN UGANDA: A POPULATION-BASED, NATIONALLY REPRESENTATIVE STUDY Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:116 (abstract no. 23) Wolfgang Hladik1, J Musinguzi2, A Opio2, W Kirungi2, J Ekwaru1, F Kaharuza1, R Downing1, R Bunnell1, and J Mermin1 Most incident HIV infections in Ugandan adults occurred among married people and those ≥25 years. At least half of new infections among married participants were acquired from their spouse. National prevention efforts should include married people because of HIV-discordance and sexual partnerships outside of marriage. |
| 124 | MEASURING THE FORCE OF THE HIV EPIDEMIC IN A RURAL AREA OF SOUTH AFRICA: THE AFRICA CENTRE Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:116 (abstract no. 124) Till Barnighausen1,2, M L Newell1,3, F Tanser1, C Mbizana1, C Wallrauch1, G Cooke1,4, Z Gqwede1, and K Herbst1 We find very high HIV incidence in a high HIV prevalence community. The Africa Centre informs understanding of the dynamics of HIV infection epidemic at both individual and population level. Effective HIV prevention interventions are urgently needed in young women and men, and in geographically targeted communities such as those situated in close proximity to major roads. |
| 125 | UTILITY OF ROUTINE VIRAL LOAD, CD4 CELL COUNT, AND CLINICAL MONITORING AMONG HIV-INFECTED ADULTS IN UGANDA: A RANDOMIZED TRIAL Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:117 (abstract no. 125) Alex Coutinho1, J Mermin2,3, J Ekwaru2, W Were2, R Bunnell2,3, F Kaharuza2, L Alexander2, P Solberg2, J Tappero2, and D Moore2,4 The use of routine CD4 cell count monitoring was associated with fewer new AIDS-defining events or mortality compared with clinical monitoring alone. These data support WHO guidelines prioritizing access to CD4 cell count measurements. |
| 126 | LONG-TERM CD4 RESPONSE TO POTENT ART AMONG ART-NAÏVE PATIENTS IN SEVERAL LOW-INCOME COUNTRIES Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:117 (abstract no. 126) Denis Nash1, M Katyal1, M Brinkhof2, S Tuboi3, P Braitstein4, E Balestre5, M May6, E Sprinz7, N Kumarasamy8, M Egger2, and The Antiretroviral Theraphy in Low Income Countries (ART-LINC) Collaboration of IEDEA These data demonstrate excellent CD4 response to ART among patients from multiple sites in resource-limited settings. The response is sustained among those remaining on ART as long as 5 years. While this is a select sample of patients with 2 or more CD4 counts after ART initiation, the data are encouraging for the long-term effectiveness of ART in resource-limited settings among those who remain on ART. |
| 127 | EVALUATION OF CLINICAL AND IMMUNOLOGIC OUTCOMES FROM THE NATIONAL ART PROGRAM IN RWANDA, 2004 TO 2005 Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:117 (abstract no. 127) Francois Ndamage1, D Lowrance1,2,3, A Rukundo1, E Kayirangwa4, F Ndagije2, D Hoover5, J Hanson6, W Lo7, A Ayaba4, and T Ellerbrock3 Rwanda’s national ART program achieved excellent 6- and 12-month retention and immunologic outcomes during the first 2 years of rapid scale-up. However, data completeness was limited. Nationally representative sampling of routinely collected data can provide important information about program quality and may be useful in resource-limited settings. |
| 128 | EARLY DETECTION OF EFFECT ON ADULT MORTALITY OF A GOVERNMENT ART PROGRAM IN RURAL KWAZULU NATAL, SOUTH AFRICA Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:118 (abstract no. 128) Till Barnighausen1,2, G Cooke1,3, K Herbst1, A Kany Kany1, and M L Newell1,4 We show a significant effect on adult mortality within 2 years of ART program start in a high-prevalence community, even with incomplete coverage of all those eligible for treatment; thus allowing a clear public health message to encourage all who need treatment to access care. The lesser impact on male mortality may be due to lower than expected uptake of ART by men, AIDS mortality in men occurring in older age groups (for whom we currently do not have HIV data) and a larger proportion of non-HIV-related deaths. |
| 129LB | HIGH HIV PREVALENCE AMONG MALES IN DISCORDANT PARTNERSHIPS IN A FULL ACCESS DOOR–DOOR VCT PROGRAM IN RURAL UGANDA Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:118 (abstract no. 129LB) E Tumwesigye1, S Asiimwe1, E Muganzi1, M Achom2, D Kabatesi2, and J Tappero2 In Bushenyi District, among couples tested for HIV, discordance is frequent, whereas condom use in discordant partnerships is not. Although HIV prevalence is lower in males than females, males in discordant partnerships are more often HIV infected than females. In high prevalence settings, couples should know their HIV status. More preventive strategies in addition to condom use need to be promoted to protect the uninfected in these high-risk partnerships and specific prevention technologies to protect females are urgently needed. |
| Session 38—Oral Abstracts Drug Delivery, Interactions and Genetic Variability |
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| 131 | LOW TENOFOVIR CONCENTRATIONS IN CEREBROSPINAL FLUID Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:118 (abstract no. 131) Brookie Best1, S Letendre1, P Koopmans2, D Clifford3, A Collier4, B Gelman5, J McArthur6, D Simpson7, E Capparelli1, R Ellis1, and the CHARTER Group TFV concentrations in the CSF are only 4% of plasma concentrations, suggesting limited active or passive transfer into the CSF, and possibly active transport out of the CSF. CSF concentrations do not exceed the wild type IC50 of TFV, and may not provide enough protection against viral replication in the CSF. |
| 132 | DRUG INTERACTION BETWEEN ANTIMALARIAL DRUGS AND LOPINAVIR/RITONAVIR Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:119 (abstract no. 132) Polina German1, S Parikh2, J Lawrence2, N Lindegardh3, P Rosenthal2, D Havlir2, E Charlebois2, G Dorsey2, and F Aweeka1 LPV/r co-administration resulted in significant but highly variable increases in LR AUC and Clast, presumably due to inhibition of CYP3A4. The increase in AUC should be considered in the context of the excellent safety profile for LR and high levels previously reported in malaria patients. The increase may also be beneficial, as LR exposure has been correlated with treatment response. These data suggest that AR/LR may be co-administered with LPV/r without dose adjustment. |
| 133 | GENETIC VARIATION IN ACCESSORY METABOLIC PATHWAYS IS ASSOCIATED WITH EXTREME EFAVIRENZ EXPOSURE IN INDIVIDUALS WITH IMPAIRED CYP2B6 FUNCTION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:119 (abstract no. 133) Julia di Lulio1, M Rotger1, R Lubomirov1, L Decosterd2, C B Eap3, and A Telenti1 In the setting of limited CYP2B6 function, functional polymorphisms in accessory metabolic pathways may contribute to extremely high EFV exposure. However, functional studies are needed to confirm these associations because of a strong confounding factor of ethnicity. |
| 134 | LONG-ACTING TMC278, A PARENTERAL DEPOT FORMULATION DELIVERING THERAPEUTIC NNRTI CONCENTRATIONS IN PRECLINICAL AND CLINICAL SETTINGS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:120 (abstract no. 134) Gerben van 't Klooster1, R Verloes1, L Baert1, F van Velsen1, M P Bouche2, K Spittaels1, J Leempoels3, P Williams1, G Kraus1, and P Wigerinck1 Long-acting TMC278 may be a useful depot formulation since single doses gave prolonged exposure to TMC278 for several months and were well tolerated, particularly when administered intramuscularly. |
| 135LB | MARAVIROC (MVC) PHARMACOKINETICS (PK) IN BLOOD PLASMA (BP), GENITAL TRACT (GT) FLUID AND TISSUE IN HEALTHY FEMALE VOLUNTEERS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:120 (abstract no. 135) J Dumond1, Kristine Patterson1, A Pecha1, R Werner1, E Andrews2, B Damle2, R Tressler2, J Worsley3, K Boggess1, and A Kashuba1 This is the first study to investigate simultaneous MVC exposure in BP, CVF and VTB. MVC exposures in CVF and VTB were higher than those observed in BP. These data indicate that MVC has the potential to be studied as an oral agent for HIV prophylaxis. |
| 136 | THE EVOLUTION OF THERAPEUTIC DRUG MONITORING IN ART Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:120 (abstract no. 136) Giovanni di Perri and S Bonora The next steps required for the further development of TDM include both old and new issues. Among the old issues, adherence of physicians to the indications resulting from TDM is one that deserves particular attention, together with an improvement of our average pharmacological knowledge. Studies on the long-term side-effects of antiretroviral drugs and their relationship with the magnitude of drug exposure are also required, as well as carefully planned clinical studies on the relevance of drug penetration in compartments and on old and new drug–drug interactions. Among the new issues, further to the clinico-pharmacological study of new drugs and drug classes, growing relevance is attributable to pharmacogenomics, whose clinical application is still in its infancy, but predictably significant in perspective. |
| Session 39—Oral Abstracts Cardiovascular Risk, Mortality and Tuberculosis Complicating HIV Infections |
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| 139 | ELEVATED LEVELS OF INTERLEUKIN-6 AND D-DIMER ARE ASSOCIATED WITH AN INCREASED RISK OF DEATH IN PATIENTS WITH HIV Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:121 (abstract no. 139) Lewis Kuller and SMART Study Group ART interruption results in significant increases in IL-6 and D-dimer. Elevated levels of D-dimer and IL-6 identify a subgroup of HIV-infected patients at high risk of death in both treatment groups. Increases in IL-6 and D-dimer may explain, in part, the increased risk of mortality and CVD in the DC group. |
| 140 | HIV ACTIVATES MARKERS OF CARDIOVASCULAR RISK IN A RANDOMIZED TREATMENT INTERRUPTION TRIAL: STACCATO Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:121 (abstract no. 140) Alexandra Calmy1, A Nguyen1, F Montecucco1, A Gayet-Ageron1, F Burger1, F Mach1, A Carr2, S Ubolyam3, B Hirschel1, J Ananworanich3,4, and for the Staccato study team There are significant differences in endothelial activation markers between patients on HAART, and patients without HAART. Acute viral replication occurring after treatment interruption is related to a change in key markers of cardiovascular risk. These changes were at least partly reversible at time of re-treatment. |
| 141 | AGE- AND SEX-SPECIFIC DEATH RATES IN ART-NAÏVE PATIENTS WITH CD4 COUNT ABOVE 350 CELLS/mm3 COMPARED WITH THE GENERAL POPULATION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:122 (abstract no. 141) Rebecca Lodwick1, K Porter2, C Sabin1, B Ledergerber3, A Cozzi-Lepri1, P Khaykin4, A Mocroft1, L Jacobson5, S de Wit6, A Phillips1, and Study Group on Death Rates at High CD4 Count in Antiretroviral Naïve Patients In HIV-infected ART-naïve people with CD4 count >350 cells/mm3, death rates tended to be raised compared with the general population. However, for the MSM risk group this was marginal, suggesting that some of the raised risk in other groups may be due to confounding by other factors. Even in this high CD4 count range, lower CD4 count and higher viral load were associated with raised mortality. Although several cohorts are linked with national death records, it is plausible that under-ascertainment or late reporting of deaths has resulted in under-estimation of death rates. |
| 142 | IMMEDIATE VS DEFERRED ART IN THE SETTING OF ACUTE AIDS-RELATED OPPORTUNISTIC INFECTION: FINAL RESULTS OF A RANDOMIZED STRATEGY TRIAL, ACTG A5164 Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:122 (abstract no. 142) Andrew Zolopa1, J Andersen2, L Komarow2, A Sanchez3, C Suckow4, I Sanne5, E Hogg6, W Powderly7, and ACTG A5164 Study Team Although there was no significant difference between immediate and deferred ART in the primary endpoint that includes both clinical and virological response, immediate ART reduced death/AIDS progression over 48 weeks. This randomized strategy trial suggests that, absent contraindications, consideration should be given to early use of ART in HIV-infected patients presenting with an acute opportunistic infections. |
| 143 | EXOGENOUS RE-INFECTION WITH MULTIDRUG- AND EXTENSIVELY DRUG-RESISTANT TB AMONG TB/HIV CO-INFECTED PATIENTS IN RURAL SOUTH AFRICA Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:122 (abstract no. 143) J Andrews1, Neel Gandhi2, P Moodley3, S Shah2, L Bohlken3, T Moll4, M Pillay3, G Friedland1, W Sturm3, and Tugela Ferry Care and Research Collaboration Exogenous re-infection with drug-resistant strains was responsible for all new drug resistance among patients in the first year after TB diagnosis. In addition to supporting medication adherence, TB control programs must urgently address infection control to reduce transmission of resistant TB and curtail the rise of MDR and XDR TB in HIV-infected patients. |
| 144 | HIV INFECTION AND DRUG-RESISTANT TB IN UKRAINE: A THREATENING CONVERGENCE OF 2 EPIDEMICS? Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:123 (abstract no. 144) I Dubrovina1, K Miskinis2, S Lyepshina3, Y Yann4, H Hoffmann5, R Zaleskis6, P Nunn7, and Matteo Zignol7 A positive association between HIV and MDR-TB epidemics is found in Donetsk Oblast, Ukraine. The overlapping of the HIV and MDR-TB epidemics is likely to result in more complex patients' management, poorer treatment outcomes, and greater disease transmission. The findings of this study call for urgent measures to improve HIV prevention, control of drug-resistant TB, collaboration between HIV and TB control activities, and infection control in congregate settings. |
| 145 | THE INFLUENCE OF TB ON EARLY MORTALITY IN THE THEMBA LETHU CLINICAL COHORT, JOHANNESBURG, SOUTH AFRICA Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:123 (abstract no. 145) Daniel Westreich1, S Badal-Faesen2, B Malope2, D Rubel2, Z Akiy2, P MacPhail2, A Van Rie1, and I Sanne2 Our results suggest that individuals receiving TB treatment are not at increased risk of early death after HAART initiation; however, individuals with additional risk factors such as low BMI and low CD4 counts may have substantially increased risks. Shorter duration of TB treatment before HAART initiation was not associated with greater risk of death in this cohort. |
| 146LB | EFFECTS OF 18-MONTH PHYSIOLOGICAL GH REPLACEMENT IN RELATIVELY GH-DEFICIENT PATIENTS WITH HIV LIPODYSTROPHY Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:123 (abstract no. 146LB) J Lo, S You, B Canavan, J Liebau, G Beltrani, P Koutkia, H Lee, and Steven Grinspoon Physiologic GH replacement significantly reduced visceral fat and truncal obesity, triglycerides, and diastolic blood pressure, and was well-tolerated. However, GH increased 2-hour glucose and had no effect on carotid IMT in patients with HIV lipodystrophy and relative GH deficiency over a long period of 18 months. |
| Session 43—Symposium Accessory Proteins and Intrinsic Resistance |
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| 147 | Vif AND APOBEC: WHAT WE KNOW Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:124 (abstract no. 147) Xiao-Fang Yu Potent anti-HIV-1 cytidine deaminases have evolved to use a conserved motif to recognize a cellular RNA that is preferentially packaged by diverse retroviruses for efficient HIV-1 targeting and suppression. |
| 148 | THE ROLE OF Vpu IN RETROVIRUS PARTICLE RELEASE Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:124 (abstract no. 148) Paul Spearman Our studies suggest a model in which Vpu interacts with a human host factor or factors involved in recycling pathways in order to enhance the efficient release of viral particles. |
| 149 | GENETIC VARIATION IN TRIM5a AND RELATED GENES Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:124 (abstract no. 149) Sara Sawyer1, M Emerman2, and H Malik2 Astonishingly, this same loop is under positive selection in the multiple cow TRIM5 genes as well, indicating that this small structural loop may be a viral recognition motif spanning a hundred million years of mammalian evolution. |
| 150 | HIV Vpr PROTEIN AS A MEDIATOR OF UBIQUITYLATION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:125 (abstract no. 150) Carlos de Noronha*, X Wen, L Casey, J Sharifi, and K Duus The level of Vpr determines whether cytoplasmic or cellular UNG2 populations will be depleted. In an infection, the quantity of Vpr present in cells depends upon the viral replication cycle. Thus UNG2 depletion may change during an infection. The efficiency of UNG2 co-immunoprecipitation with Vpr and Vpr mutants does not predict the efficiency of UNG2 degradation, demonstrating that the capacity of Vpr to engage UNG2 is not sufficient to promote depletion. Finally, HIV2 Vpr, while it engages the ubiquitin ligase complex to cause cell cycle arrest, does not appear to promote UNG2 depletion. Together these findings provide insights into the function of Vpr as a mediator of ubiquitination that will aid in the identification of other targets like the one responsible cell cycle arrest. |
| Session 44—Symposium Frontiers in Vaccine Research |
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| 151 | ADVANCES IN VACCINES SCAFFOLDS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:125 (abstract no. 151) Bill Schief By displaying HIV epitopes in non-HIV scaffolds, we hope to bypass mechanisms of humoral evasion and rather induce the immune system to make broadly neutralizing antibodies. These “epitope-scaffolds” are designed with atomic detail to stabilize the antibody-bound conformation of the epitope on the surface of the scaffold. We are addressing several HIV epitopes with this approach. |
| 152 | LESSONS LEARNED FROM HIV-1 ENVELOPE GLYCOPROTEIN IMMUNOGENICITY ANALYSIS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:125 (abstract no. 152) Mattias Forsell1,2, B Dey1, A Moerner3, G Voss4, R Thorstensson3, P Kwong1, G Shaw5, J Mascola1, G Karlsson Hedestam2,3, and R Wyatt1 The effect of rational protein design on the biophysical and antigenic properties and antibody responses to selected immunogens will be discussed. |
| 153 | IDENTIFICATION AND CHARACTERIZATION OF TRANSMITTED AND EARLY FOUNDER VIRUSES IN PRIMARY HIV-1 INFECTION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:126 (abstract no. 153) B Keele1, E Giorgi2,3, J Salazar-Gonzalez1, F Gao4, R Swanstrom5, M Busch6, B Haynes4, B Korber2,7, B Hahn1, and George Shaw1 SGA and sequencing of HIV-1 RNA in acute and early infection represents a powerful experimental strategy for identifying transmitted and early founder viruses and for characterizing molecular mechanisms responsible for immune evasion by HIV-1 in naïve individuals and in vaccinated. |
| 154 | ATTENUATED SIV MODELS AND PROTECTION FROM PATHOGENIC HETEROLOGOUS CHALLENGES Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 154) James Hoxie1, A Jordan1, B Haggarty1, J Romano1, M Piatak2, J Lifson2, D Montefiori3, M Marsh4, and P Fultz5 Thus, ablation of the GYxxØ trafficking signal by the ΔGY mutation renders SIVmac239 highly attenuated in vivo, and infection by ΔGY virus enables animals to control a highly pathogenic heterologous challenge SIV. This novel model should be informative in identifying pathological and immunologic correlates of attenuation and protection, and in establishing the underlying mechanism for this effect at the viral and cellular level. |
| Session 45—Symposium Individualizing Patient Management |
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| 155 | OPTIMIZING PATIENT MANAGEMENT IN RESOURCE-LIMITED SETTINGS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:126 (abstract no. 155) Jonathan Mermin To implement ART effectively, adherence must be supported within the context of mundane obstacles, such as limited access to health facilities and transportation, and few highly trained health care personnel. To assess patients’ eligibility effectively and initiate appropriate ART regimens, consideration must be given to issues, such as toxicity, potential pregnancy, concurrent treatment for other illnesses, malnutrition, adherence, and drug efficacy. |
| 156 | INDIVIDUALIZING PATIENT MANAGEMENT: HOST GENETICS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:127 (abstract no. 156) Jacques Fellay It is expected that new comprehensive, genome-wide approaches will profoundly change the landscape of knowledge in the near future, allowing for better individualization of drug prescription. In addition, host genetic research will identify targets for new therapeutics by improved knowledge of basic cellular biology. |
| 157 | INDIVIDUALIZED MANAGEMENT OF THERAPY: VIROLOGIC COMPLICATIONS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:127 (abstract no. 157) Carlo-Federico Perno Taken together, the refining and proper utilization of advanced diagnostic tools represents a key element to individualize the therapy to each patient. A widespread strategy aimed at extending their use in clinical practice may be warranted in this setting. |
| 158 | INDIVIDUALIZED MANAGEMENT OF THERAPY: THE ISSUE OF COMPLICATIONS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:127 (abstract no. 158) Jennifer Hoy There is little to no information currently available for the risk of these complications with the newer agents, and insufficient long-term safety data for the agents from new drug classes to confidently place them in individualized treatment strategies for the purpose of overcoming treatment toxicity. Continued research is needed to consistently assess adverse reactions to newly available antiretroviral agents so as to enhance approaches to avoid, minimize and manage short- and long-term treatment-related complications. |
| Session 46—Poster Abstracts Cellular Co-factors |
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| 200 | VISUALIZATION OF THE HIV HOST PROTEIN INTERACTION NETWORK Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:129 (abstract no. 200) Jonathan Dickerson1, J Pinney1, R Ptak2, W Fu2, B Sanders-Beer2,3, and D Robertson1 Visualisation of the HIV-human protein interaction network forms the basis of a detailed map for tracking both direct and indirect molecular interactions involved in HIV-1 replication and pathogenesis. Incorporation of additional information, for example, expression data, cell-type and known drug targets, will place the interactions into their biological context. Ultimately this has the potential to accelerate the development of more effective and sophisticated antiviral and vaccine interventions. This integrative methodology mirrors the shift in molecular biology from focussing on a small set of components to having an understanding and appreciation of an entire system. |
| 201 | ADAM10: A CELLULAR METALLOPROTEASE REQUIRED AT OR JUST PRIOR TO HIV INTEGRATION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:129 (abstract no. 201) B Friedrich1, J Murray2, D Rubin3, T Hodge2, and William O'Brien1 Collectively, our data indicate that ADAM10 acts at or just prior to HIV integration. Confirmation of ADAM10 effects in primary macrophages is a critical step in the development of specific therapies that target actions of cellular proteins. The absence of cytotoxic effects associated with down-regulation in primary macrophages suggests that ADAM10 may not be essential for the cell and may provide a unique target for therapeutic intervention. |
| 202 | TRANSIENT KNOCKDOWN OF THE VON HIPPEL LINDAU BINDING PROTEIN 1 IN HELAP4 CELLS ENHANCES HIV-1 REPLICATION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:129 (abstract no. 202) Wannes Thys, F Christ, J De Rijck, and Z Debyser The use of RNAi as a tool for the validation of potential cellular co-factors of HIV-1 replication is now widely accepted. Multiple reports over the past years have cautioned for interpreting results of siRNA-mediated knockdown and asked for using multiple controls. Using multiple specific siRNA targeting VBP1, we observed a 2-fold increase in HIV-1 replication in contrast with recently published data. The reason for the discrepancy is at present not clear. VBP1 may well act as a cellular restriction factor instead of a co-factor of HIV-1. |
| 203 | ACTIVATOR PROTEIN 1 SYNERGIZES WITH NF-κB TO ACTIVATE LATENT HIV PROVIRUS TRANSCRIPTION FOLLOWING T CELL RECEPTOR ACTIVATION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:130 (abstract no. 203) Joseph Hokello, Y K Kim, R Pearson, and J Karn We conclude that latent HIV provirus transcription is a highly dynamic process which cycles on a time-scale of minutes to hours, tightly regulated by multiple transcription factors. The combination of NF-κB and AP-1 are used to modulate the duration and magnitude of the HIV transcriptional response. |
| 204 | OVEREXPRESSION OF NF90 OR ITS MUTANTS TOGETHER WITH ITS N-ter REGION, DECREASE REV EXPORT ACTIVITY AND HIV-1 REPLICATION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:130 (abstract no. 204) Claudia Patino1, X Zapata1, G St Laurent2, A Kumar2, D Hernandez-Verdun3, and S Urcuqui-Inchima1 We therefore propose that NF90 overexpressed together with its N-ter region, not only decreases Rev export activity, but also blocks HIV-1 replication. Other studies are being undertaken to confirm these results. |
| 205 | THE RECEPTOR TYROSINE KINASE RON REPRESSES HIV-1 TRANSCRIPTION BY TARGETING RNA POLYMERASE II PROCESSIVITY Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:130 (abstract no. 205) A Klatt1, Z Zhang2, P Kalantari1, P Hankey1, D Gilmour1, and Andrew Henderson3 These results indicate that RON represses HIV transcription at multiple transcriptional checkpoints—including initiation, elongation, and chromatin organization—and are the first studies to show that cellular signaling pathways target RNA Pol II pausing to repress gene expression. |
| 206 | DOMINANT NEGATIVE CYCLIN T1 PROTEIN THAT INHIBITS HIV TRANSCRIPTION BY SPECIFICALLY DEGRADING Tat Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:131 (abstract no. 206) Julie Jadlowsky1, K Fujinaga1, M Nojima1, M Geyer2, and T Okamoto3 There is an intimate interplay between host and viral factors involved in propagation of HIV-1 virions and transcription of viral mRNAs. Insights into these processes could lead to new targets for ART. Our CycT1-U7 mutant inhibits HIV transcription by promoting rapid and specific degradation of Tat. Understanding the critical interactions between host and viral factors could lead to targeted development of novel transcription inhibitors. |
| 207 | PRMT6 FINE-TUNES LOCALIZATION PATTERNS OF HIV-1 PROTEINS TAT AND REV Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:131 (abstract no. 207) Rita Schildknecht, C Invernizzi, S Colby-Germinario, K Dahl, J Martinez, B Spira, B Brenner, and M Wainberg Intracellular PRMT6 levels primarily fine-tune the HIV-1 life cycle by subtly altering the localization patterns of Tat and Rev. This may slow down the switch from the early to the late phase of the viral life cycle in order to enhance overall viral replication. |
| 208 | ROLES FOR IST1 IN VPS4 REGULATION AND HIV-1 BUDDING Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:131 (abstract no. 208) Monika Bajorek, E Morita, J Skalicky, M Babst, and W Sundquist Our results support the conclusion that human IST1 and VPS4 can act in concert as: IST1 binds VPS4; VPS4 adenosine triphotatase activity controls IST1 localization; both proteins are required for efficient Hela cell cytokinesis; and IST1 over-expression inhibits HIV-1 budding, presumably by diminishing the enzymatic activity of the VPS4 adenosine triphosphatase or competitively inhibiting ESCRT-III binding. |
| 209 | FUNCTIONAL ROLE OF ALIX IN HIV-1 REPLICATION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:132 (abstract no. 209) Ken Fujii, U Munshi, S Ablan, and E Freed The results of this study indicate that p6–Alix binding plays an important role in HIV-1 replication, particularly in primary cell types that are physiologically relevant for HIV-1 replication in vivo. |
| 210 | STRUCTURE OF YEAST Vps4p BY ELECTRON MICROSCOPY AND X-RAY CRYSTALLOGRAPHY Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:132 (abstract no. 210) Malgorzata Gonciarz1, Z Yu2, F Whitby1, C Kieffer1, G Jensen2, W Sundquist1, and C Hill1 Electron cryomicroscopy reconstructions of Vps4 reveal a structure comprising 2 stacked hexameric rings that adopt different conformations. Dimerization and oligomerization of yeast Vps4p is mediated by interfaces that are overlapping but distinct. |
| 211 | ROLE OF KINASES OF THE PIKK FAMILY IN RETROVIRAL REPLICATION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:132 (abstract no. 211) Y Yang, V Guen, and Lionel Berthoux Kinases of the PIKK pathway seem to play a role in early HIV-1 replication in a cell type-specific fashion. Identification of cellular proteins important for post-integration DNA repair might lead to the validation of novel pharmacological targets. |
| Session 47—Poster Abstracts Cellular Restrictions |
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| 212 | APOBEC3G PROTEIN EXPRESSION IN BLOOD RESTING AND ACTIVATED CD4+ AND CD8+ T CELLS. ITS EFFECT ON SUSCEPTIBILITY TO HIV INFECTION AND PROGRESSION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:133 (abstract no. 212) H Oliva1, Montserrat Plana1, A Lopez1, J Martinez-Navio2, R Franco2, J Miro1, F Garcia1, J Gatell1, N Navaratnam3, and T Gallart1 Data suggest that a low A3G expression in CD3+CD4+ T cells, the main cell target where HIV replicates, is associated with a low susceptibility to HIV-1 infection. This is consistent with the fact that low A3G expression in blood CD4 T cells correspond to a resting stage, which involves the low molecular mass form of A3G that is highly active against HIV-1. |
| 213 | TARGET CELL APOBEC3C CAN INDUCE LIMITED G-TO-A MUTATION IN HIV-1 Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:133 (abstract no. 213) K Bourara1, T Liegler2, and Robert Grant1,2 A3C is necessary and sufficient for G-to-A mutations in some, but not all, HIV-1 strains. A3C-induced mutations occur at levels that allow replication to persist and may therefore contribute to viral diversity. Inhibitors of A3C decrease viral mutation in cell culture, and may represent a novel strategy for delaying viral escape from immune or antiretroviral inhibition. |
| 214 | DETERMINANTS OF HIV-1 VIF REGULATION OF APOBEC3 PROTEINS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:133 (abstract no. 214) W Zhang, Anna Maria Niewiadomska, and X F Yu These results indicate that various distinct interfaces between HIV-1 Vif and APOBEC3 proteins are important for Vif-mediated degradation of substrate molecules. This information has implications for the design of multiple interference strategies blocking the interactions between HIV-1 Vif and various APOBEC3 proteins, thus representing attractive targets for anti-viral drug development. |
| 215 | THE ANTI-HIV-1 POTENCY OF APOBEC1 CYTIDINE DEAMINASE FROM SMALL ANIMAL SPECIES Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:134 (abstract no. 215) Terumasa Ikeda1, T Ohsugi2, T Kimura1, S Matsushita3, Y Maeda1, S Harada1, and A Koito1 Several APO1 can suppress HIV-1 replication through cytidine deaminase-dependent mechanism, which acts on both first-strand cDNA synthesized during reverse transcription and the genomic RNA in HIV-1 virion. Our results also indicate the existence of a deaminase-independent restriction mechanism by APO1. These findings reveal that APO1 may function as the defense mechanism regulating retroviruses and retroelements in a wide range of mammalian species. |
| 216 | A SINGLE AMINO ACID OF THE HIV-2 CAPSID DETERMINES ITS REPLICATION IN THE PRESENCE OF CYNOMOLGUS MONKEY AND HUMAN TRIM5α Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:134 (abstract no. 216) Haihan Song1, E Nakayama1, M Yokoyama2, H Sato2, J Levy3, and T Shioda1 These results indicate that the single amino acid at the 120th position of the HIV-2 CA is a major determinant for sensitivity of the virus to cynomolgus monkey and human TRIM5α. |
| 217 | ANALYSIS OF THE ROLE OF CYTOPLASMIC BODIES IN TRIM5α RESTRICTION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:134 (abstract no. 217) Cindy Danielson, E Campbell, M McRaven, and T Hope This work identifies a stretch of amino acids between the coiled-coil domain and C-terminal SPRY domain that appears to mediate the ability of rhTRIM5α to accumulate in cytoplasmic bodies. This stretch of amino acids lies within L2 domain, the deletion of which has previously been reported as being required for TRIM5α-mediated restriction. We hope to use this observation as a tool to determine if the ability of TRIM5α to form cytoplasmic bodies is genetically separable from its ability to restrict viral infection. These studies therefore may clarify the importance of cytoplasmic bodies regarding the function of TRIM5α as a restriction factor. We also find that cytoplasmic bodies are formed as a dynamic and transient response to virus exposure. Future studies will seek to dissect this response in an effort to better understand the process of restriction. |
| 218 | USING A RESTRICTION-DEFICIENT CELL LINE IN THE SEARCH FOR CELLULAR PROTEINS IMPORTANT FOR TRIM5α ACTIVITY Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:134 (abstract no. 218) Julie Berube, A Bouchard, and L Berthoux D17 cells provide a poor environment for the retroviral restriction mediated by TRIM5α and TRIMCyp. We hypothesize that a cellular factor required for TRIM5α or TRIMCyp antiviral activity is inadequately expressed in D17 cells. We are currently using genetic screens to identify such a factor. |
| Session 48—Poster Abstracts Viral Accessory Genes |
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| 219 | CO-VARIATION NETWORKS IN HIV-1 NEF SEQUENCES FROM PHYLOGENETIC AND MIXTURES ANALYSIS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:135 (abstract no. 219) Art Poon1, R Harrigan2, and S Frost1 We obtain detailed networks of co-variation in Nef at 2 levels of the virus population, which provides a foundation for mapping the multiple functions of this protein to specific residues that is robust to founder effects. |
| 220 | NEF PROTEINS DERIVED FROM HIV-1 SUBTYPES C AND F FAIL TO UP-REGULATE INVARIANT CHAIN CELL SURFACE EXPRESSION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:135 (abstract no. 220) Gabriela Turk1, P Benaroch2, and H Salomon1 It has been previously demonstrated that Nef-mediated up-regulation of Ii is a conserved function among HIV-1, HIV-2, and SIVmac. Moreover, it has been suggested that failure to up-regulate Ii could contribute to slower disease progression. Here, we showed that subtype C- and F-derived Nef proteins have a diminished capacity to up-regulate Ii cell surface expression. Nef domains previously reported as being involved in Ii up-regulation were conserved among the alleles analyzed here. Further structural and functional analyses of these Nef variants will help to shed light over the mechanisms governing Nef-mediated Ii up-regulation, which still remain to be elucidated. |
| 221 | NUCLEO-CYTOPLASMIC TRANSPORT OF VPX PLAY A CRITICAL ROLE IN HIV-2/SIV REPLICATION IN NON-DIVIDING CELLS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:135 (abstract no. 221) P Singhal1, P Rajendra Kumar1, and Sundarasamy Mahalingam1,2 Vpx shuttles between nucleus and cytoplasm and the nucleo-cytoplasmic transport is modulated by phophorylation. Nuclear import of Vpx is critical for the efficient transport of viral genome into the nucleus in non-dividing cells. In contrast, export of Vpx from nucleus is mediated by a novel tryptophan-rich export signal and regulates the packaging of Vpx into the newly assembled virions, which is important for the establishment of virus infection in the new target cells. |
| 222 | CTIP2 INHIBITS HIV-1 Vpr-INDUCED CELL CYCLE ARREST BY REPRESSING p21WAF1 GENE EXPRESSION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:136 (abstract no. 222) Stella Suzanne1, T Cherrier1, C Marban1, B Samah2, R Mukerjee3, C Schwartz1, S Zeichner4, D Aunis1, C Van Lint5, and O Rohr1 Altogether, our results suggest that CTIP2 is a constitutive repressor of the p21 gene promoter and thus, a potent inhibitor of HIV-1 Vpr function. We reveal that CTIP2-mediated anti-HIV activity is not restricted to HIV-1 gene transcriptional silencing but results from conjunctions of multiple repressive activities targeting the viral and the cellular genomes. |
| 223 | FUNCTIONAL PROPERTIES OF NATURALLY OCCURRING TRUNCATED FORMS OF HIV-1 Vif Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:136 (abstract no. 23) Mohammad Khan1, R Goila-Gaur1, N Choudry2, E Miyagi1, S Kao1, and K Strebel1 Thus, sequences near the N-terminus of Vif may be required for intracellular degradation of APO3G but may be dispensable for the ability of Vif to prevent packaging of APO3G into HIV-1 virions. |
| 224 | HIV-1 Vif CAUSES G2 CELL CYCLE ARREST VIA THE p53 PATHWAY Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:136 (abstract no. 224) Taisuke Izumi, A Takaori-Kondo, K Shirakawa, K Io, M Matsui, and T Uchiyama We demonstrate the functional interaction between the Vif protein and the p53/MDM2 pathway. Activation of p53 pathway is the molecular mechanisms involved in G2 cell cycle arrest induced by Vif. |
| 225 | GENETIC PATTERNS ASSOCIATED WITH FUNCTIONAL ADAPTATION OF Nef TO DOWN-REGULATE MHC-I AND EVADE CTL Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:137 (abstract no. 225) Martha Lewis, P Lee, A Rusmevichientong, L Hultin, and O Yang These results demonstrate strong evolutionary pressures on Nef via its functional role in immune evasion. The lack of consistent polymorphisms under selection indicate the plasticity of this small protein to adapt to maintain function through diverse genetic pathways, and the strong purifying selection by CTL highlights the significant functional pressure exerted by CTL. |
| 226 | HIV-1-MEDIATED CELL CYCLE ARREST AND APOPTOSIS IN HUMAN CD4+ T CELLS IS INDEPENDENT OF HIV-1 Env AND Vpr Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:137 (abstract no. 226) Alicja Dabrowska, N Kim, and A Aldovini Our results show that HIV-1-mediated cytopathicity of human CD4+ T cells is Vpr- and Env-independent. We confirm the previously reported role of Vpr in cell cycle arrest and present evidence for the pathway involved in this arrest and for the Vpr-independent G0 arrest in cells infected with HIV-1. G0 entry by HIV infected CD4+ T cells may be critical for the virus latency in the host cells. |
| 227 | IMPORTANCE OF SIVmac239 Vpr INDUCED CELL CYCLE ARREST FOR DISEASE PROGRESSION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:137 (abstract no. 227) Sandra Mueller1,2, B Scholz3, S Weiler4, N Stolte-Leeb5, C Stahl-Hennig5, B Fleckenstein3, S Lang6, and German Competence Network on HIV/AIDS Vpr-induced cell cycle arrest seems to be important for disease progression and pathogenicity, at least in the SIVmac239/rhesus macaque model. |
| 228 | Vpr-MEDIATED INHIBITION OF IL-12 AND DISRUPTION OF UPSTREAM SIGNALING RECEPTORS CD14, TLR4, AND THE GLUCOCORTICOID RECEPTOR Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:138 (abstract no. 228) Fiona Frappier1,2, J Boucher1,2, A O'Connor1,2, and J Angel1,2 HIV and Vpr affect upstream receptors that mediate IL-12 production. This study furthers the understanding of the link between the glucocorticoid and cell-mediated immune pathways. Characterizing the cellular mechanisms by which HIV inhibits IL-12 production will lead to a better understanding of how cell-mediated immune responses are inhibited by HIV infection and have the potential to lead to the development of novel immune based therapies. |
| Session 40—Poster Discussion Poster Discussion: New Insights into APOBEC Proteins |
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| 229 | DEAMINATION IN 3D: INTRA- AND INTERSEGMENTAL TRANSFER OF APOBEC3G CYTIDINE DEAMINASE Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:138 (abstract no. 229) Roni Nowarski, M Kotler, and E Britan A3G target location is facilitated by 3-dimensional translocation on ssDNA. The translocation mechanism is based on intra- and intersegmental transfer which direct the observed deamination patterns. Locally, A3G deaminate 1 cytidine per binding event; however it maintains intimate contact with the DNA and performs processive catalysis of targets located close or far apart on the DNA contour. Elucidating the mechanism of A3G translocation on DNA will help understanding the role of APOBEC proteins in retroviral restriction and might prove useful for designing future antiviral strategies. |
| 230 | APOBEC3G’S CYTOPLASMIC LOCALIZATION IS ACTIVELY REGULATED BUT NOT REQUIRED FOR HIV-1 RESTRICTION Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:138 (abstract no. 230) Mark Stenglein and R Harris These findings demonstrate that A3G’s strict cytoplasmic localization is actively governed and genetically separable from its ability to limit HIV replication. A3G’s strict cytoplasmic localization may serve another purpose, perhaps to protect the cellular genome from the enzymatic activity of this DNA mutator. |
| 231 | ENZYMATICALLY ACTIVE APOBEC3G IS REQUIRED FOR EFFICIENT INHIBITION OF HIV-1 Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:139 (abstract no. 231) E Miyagi, S Opi, H Takeuchi, M Khan, R Goila-Gaur, S Kao, and Klaus Strebel These results suggest that the antiviral activity of deaminase-defective APO3G was significantly lower than that of wild type APO3G. We conclude that efficient inhibition of vif-defective HIV-1 requires catalytically active APO3G. |
| 232 | DISTINCT PACKAGING MECHANISMS OF HUMAN CYTIDINE DEAMINASE APOBEC3 PROTEINS INTO HIV-1 VIRIONS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:139 (abstract no. 232) Lindi Tan, T Wang, and X Yu Human A3 proteins have evolved to use distinct packaging mechanisms to target retroviruses. |
| 233 | EFFECT OF IMPAIRED PROCESSIVITY OF HIV-1 REVERSE TRANSCRIPTASE ON THE G-TO-A MUTATION RATE INDUCED BY APOBEC-3G/-3F Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:139 (abstract no. 233) Stefanie Knoepfel, P Rauch, N Salisch, K Allers, P Huelsmann, and K Metzner High reduction of the rate of DNA synthesis (M184I and K65R/M184V-RT) leads to an increase of the amount of G-to-A mutations induced by APOBEC-3G/-3F, whereas moderate reduction of RT processivity (M184V) has no effect on the amount of G-to-A mutations suggesting that APOBEC-3G/-3F induces G-to-A mutations in a time-dependent manner. The high amount of non-mutated clones derived from PBMC suggests that additional antiretroviral mechanisms of APOBEC proteins besides their deamination activity are responsible for the inhibition of vif-deficient viruses. |
| 234 | PROTEIN KINASE A-MEDIATED PHOPHORYLATION OF APOBEC3G ANTAGONIZES ITS DEGRADATION BY Vif Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:139 (abstract no. 234) Kotaro Shirakawa, A Takaori-kondo, T Izumi, K Io, M Matsui, and T Uchiyama PKA-mediated phophorylation of APOBEC3G antagonizes its degradation by Vif. |
| Session 50—Poster Abstracts Viral Replication Cycle: Molecular Studies |
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| 235 | DIMERIZATION OF HIV-1 SPLICED RNA IN VITRO Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15:140 (abstract no. 235) Lucile Sinck1, D Richer1, J Howard2, M Alexander2, D Purcell2, R Marquet1, and J C Paillart1 Together, our results show that HIV-1 spliced RNA homo- and heterodimerize with gRNA through the dimerization initiation site. It also supports a model in which RNA dimerization would occur during transcription in the nucleus, thus playing a major role in splicing, transport,and localization of HIV-1 RNA. |
| 240 | Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 240) |
| Session 51—Poster Abstracts Viral Envelope: Tropism Co-receptor Studies |
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| 241 | Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 241) |
| 252 | Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 252) |
| Session 52—Poster Abstracts Viral Fitness, Evolution and Recombination |
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| 253 | Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 253) |
| 263 | Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 263) |
| Session 53—Poster Abstracts HIV-1-Macrophage Studies |
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| 264 | Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 264) |
| 268 | Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 268) |
| Session 54—Poster Abstracts Co-infection: Virus/Virus Interactions |
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| 269 | Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 269) |
| 273 | Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 273) |
| Session 55—Poster Abstracts Viral Reservoirs |
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| 274 | Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 274) |
| 280b | Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 280b) |
| Session 56—Poster Abstracts Viral Transmission: Molecular Studies |
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| 281 | Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 281) |
| 294 | Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 294) |
| Session 57—Poster Abstracts Factors Impacting Disease Progression |
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| 297 | INTERFERON-γ GENOTYPE (874T>A) IS ASSOCIATED WITH CCR5 EXPRESSION IN HIV+ PATIENTS Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 297) N Liptrott, B Chandler, S Khoo, D Back, and Andrew Owen The relationship between the change in expression of transporters and HIV co-receptors in response to cytokines supports the hypothesis that similar mechanisms regulate their expression. The combined effect of cytokines on transporter and co-receptor expression may have important pharmacological and virological implications. The 874T >A allele was significantly associated with CCR5 expression and further studies are now required to assess the impact on disease progression. |
| 318 | Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 318) |
| Session 59—Poster Abstracts Studies on Viral Evolution in vivo |
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| 319 | Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 319) |
| 323 | Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 33) |
| Session 60—Poster Abstracts CTL Studies and Consequences of Immune Escape |
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| 324 | Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 324) |
| 335 | Conf Retroviruses Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 335) |