1st National Conference Human Retroviruses and Related Infections


Washington, D.C. - December 12-16, 1993

Cite as: Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: abstract no. xx

Session 8—Retroviral Resistance to Antiviral Agents
1 BASELINE PREVALENCE AND CLINICAL SIGNIFICANCE OF ZIDOVUDINE RESISTANCE MUTATIONS IN HIV-1 ISOLATES FROM PATIENTS PARTICIPATING IN ACTG PROTOCOL 116B/117
Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 1)
Kuritzkes DR, Welles S, Johnson VA, D'Aquila RT, Richman DD, Crumpacker CS, Reichlederfer P, Degruttola V, Japour AJ
In a multiple regression model that included CD4 count, virus phenotype (SI/NSI), and diagnosis of AIDS at baseline, the presence of the 215 mutation was not an independent risk factor for clinical progression. Additional analyses are being performed to determine whether the combined presence of mutations at codon 41 and 215 improves the prognostic power of this test.
2 CHANGE TO DDI IMPROVES CD4 COUNT AND PREVENTS IN VITRO RESISTANCE TO AZT REGARDLESS OF HIV PHENOTYPE AMONG HIV+ INDIVIDUALS WITH CD4'S 200 TO 500/MM3 TREATED WITH AZT FOR ≥ 6 MONTHS
Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 2)
Montaner JS, Wainberg M, Rachlis A, Gill J, Beaulieu R, Schlech W, Tsoukas C, O'Shaughnessy M, Raboud J, Smaldone L
Our results demonstrate that an early change to ddI leads to a sustained increase in CD4 count, prevents in vitro resistance and often leads to a decrease in IC50 if AZT resistance is present. These effects are independent of viral phenotype.
3 ZIDOVUDINE (AZT) RESISTANCE IS TEMPORALLY ASSOCIATED WITH CLINICAL FAILURE IN PATIENTS ON AZT THERAPY
Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 3)
Mayers DL, Wagner KF, Chung RC, Lane JR, Vahey MT, White FA, Ruiz NM, Hicks CB, Weislow OS, Gardner LI
Genotypic evidence of AZTR virus emerges prior to CD4 decline in patients on AZT monotherapy. 50% of pts who develop codon 215 mutations experience significant CD4 decline in the next 12 months. A model relating host and virus factors to AZTR and CD4 decline will be presented.
4 BEHAVIOR OF CODON 74 AND 215 POL GENE MUTATIONS IN 62 AZT EXPERIENCED PATIENTS ON ddI MONOTHERAPY
Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 4)
Kozal M, Winters M, Shafer R, Kroodsma K, Katzenstein D, Merigan T
In patients changed from AZT to ddI, the codon 74 MUT occurred frequently and usually with a persisting codon 215 MUT. Patients with a codon 74 MUT had a greater serum virus burden than patients WT at codon 74. The high frequency of both 215 and 74 MUT suggests a replicative advantage for this genotype during ddI monotherapy. In contrast, combination therapy with AZT/ddI (ACTG 143) prevents mutation at codon 74 but not at 215. This may be explained by a replicative advantage during AZT/ddI therapy for virus having only the codon 215 MUT as compared to having both codon 74 & 215 MUT.
5 AMINO TERMINAL CLUSTERING OF MUTATIONS IN THE HIV-1 REVERSE TRANSCRIPTASE FOLLOWING ddI THERAPY
Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 5)
Chatis PA1,2, Japour AJ1, Mayers DL3, McCutcheon FE4, Kim L1, Page C3, Crumpacker CS1
Three viral isolates with reduced susceptibility to ddI each contained changes near to codon 74, namely, at codons 65, 70, and 72. Therefore, a clustering of mutations in the amino terminal end of the HIV-1 RT between codons 65 and 74, a region that corresponds to the ß3- ß4 connecting loop, appears to be associated with decreased susceptibility to ddI.
6 RECOVERY OF HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 RECOMBINANTS THAT POSSESS DUAL DRUG RESISTANCE FOLLOWING FUSION OF CELLS INFECTED WITH DISTINCT SINGLE DRUG-RESISTANT VARIANTS
Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 6)
Gao Q, Fang H, Gu Z, Wainberg MA
The viral progeny of these hybrids contained, as expected, mutations at either site 184, in the case of 3TC, or sites 70 and 215, for AZT. In 3 instances, viral progeny were 40-50 fold resistant against AZT and 90-120 fold against 3TC, in comparison with wild-type HXB2-D. Sequencing and PCR analysis showed that these dually resistant variants contained the expected mutations at each of sites 70, 184 and 215 or, alternatively at sites 184 and 215 only.
7 PHENOTYPIC SUSCEPTIBILITY OF HIV-1 RT CONTAINING SUBSTITUTIONS WHICH ENGENDER RESISTANCE TO NUCLEOSIDE AND NONNUCLEOSIDE INHIBITORS
Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 7)
Byrnes V, Blahy O, Condra J, Gotlib L, Graham D, Long W, Quintero J, Rhodes A, Roth E, Sardana V
The apparent phenotypic interactions that occur among co-expressed RT mutations reflect significant structural and functional flexibility by the enzyme which allows the virus to be resistant to various combinations of RT inhibitors.
8 EVALUATION OF THE AMINO ACID 215 GENOTYPE OF HIV-1 REVERSE TRANSCRIPTASE AND VIRAL LOAD IN THE PLASMA OF PATIENTS DURING NEVIRAPINE MONOTHERAPY OR NEVIRAPINE/ZDV COMBINATION THERAPY
Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 8)
Eastman PS, Richman D, Urdea M, Kolberg J
In all patients, nevirapine therapy produced a dramatic decline in the aa 215 WT population. Preliminary data suggest that nevirapine preferentially affects the aa 215 WT population in the plasma.
9 REDUCTION OF PLASMA HIV VIRAL LOAD DURING ddI/ZDV COMBINATION THERAPY IN THE PRESENCE OF ZDV RESISTANCE
Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 9)
Holodniy M1, Eastman S2, Mole L1, Margolis D1, Moss J1, Urdea M2, Kolberg J1
The addition of ddI to ZDV therapy is well tolerated and results in significant falls in plasma RNA as assessed by bDNA assay and significant increases in CD4 count for at least 6 months. Preliminary data suggest that the presence of ZDV resistant virus in plasma is not affected by the addition of ddI.
10 ACQUISITION OF 3TC RESISTANCE MUTATIONS COINCIDES WITH AN INCREASE IN VIRAL LOAD
Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 10)
Boucher C1, Schuurman R1, Nijhuis M1, Van Leeuwen R1, Danner S1, Kaye S2, Mulder J3, Sninsky J3, Kwok S3
These data suggest that inhibition of viral replication by 3TC can decrease viral load within days. In addition, increase in viral load during therapy may serve as an indirect measure of antiviral resistance. Moreover, the turnover from wild type to mutant viruses indicates that the half life of viral particles in vivo can be short and that persistent infection with HIV is an extremely dynamic process.
Session 9—Virology I
11 THE CYTOPLASMIC DOMAIN OF CD4 CONTAINS A VPU-SENSITIVE ELEMENT
Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 2)
Strebel K, Willey R
We found that transfer of CD4 cytoplasmic sequences into CD8 resulted in Vpu- dependent degradation of the CD8/CD4 chimeric proteins. In contrast, transfer of other portions of CD4 into CD8 did not result in Vpu-dependent destabilization of the resulting chimeras. Therefore, sequences present in the cytoplasmic domain of CD4 are necessary and sufficient to confer sensitivity to Vpu.
12 STRUCTURAL AND FUNCTIONAL ANALYSIS OF THE HYDROPHOBIC ANCHOR DOMAIN OF THE HUMAN IMMUNODEFICIENCY VIRUS TYPE-1 VPU PROTEIN
Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 12)
Friborg J, Daniel N, Yao XJ, Cohen EA
These mutants were tested for membrane association in an in vitro transcription- coupled translation and translocation system in presence of canine pancreatic microsomal membranes. We have defined two regions with predicted alpha-helix structures (sequences De 7-Ala 14 and Val 20-Ser 23) required for membrane association. These vpu mutants were introduced into an infectious molecular clone of HIV-1 and assessed for vpu biological activity. The effect of these mutations on vpu-facilitated virion release and delayed cytopathic effect will be discussed.
13 VPU-DEPENDENT VIRUS RELEASE IS CELL TYPE SPECIFIC AND MAY INVOLVE AN INTERACTION WITH A CELLULAR PROTEIN
Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 13)
Geraghty RJ1, Callahan M1, Harper W2, Panganiban AT1
We have found that Vpu is necessary for virus release from a human cell line and dispensable for virus release from a simian cell line. This observation suggests that Vpu may function via an interaction with a cellular factor. The nature of the gene products produced from these cDNAs, the potential interaction between these gene products and Vpu, and the potential interaction of Vpu with viral proteins is currently under investigation.
14 THE ANCHOR AND CYTOPLASMIC DOMAINS OF CD4 ARE REQUIRED FOR VPU INDUCED PROTEOLYSIS OF CD4 IN THE ENDOPLASMIC RETICULUM
Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 14)
Raja NU, Vincent MJ, Jabbar MA
Further analyses have revealed that the anchor domain of CD4 appear to provide initial 'interaction motif' through which the vpu protein could recognize sequences or structural determinants in the cytoplasmic domain of CD4. We will discuss the mechanism by which Vpu induces the proteolysis of CD4 and chimeric proteins in the endoplasmic reticulum.
15 CHARACTERIZATION AND UTILIZATION OF THE SHIV ANIMAL MODEL: THE ROLE OF VPU AND HIV-1 ENV VARIATION AND IMMUNE ESCAPE IN SHIV-INFECTED MACAQUES
Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 15)
Li J1, Lord C2, Letvin N2, Sodroski J1
Does vpu have a contribution in this animal model? (2) Does SHIV evade the immune response through env variation? Data on these issues and others will be presented.
16 REQUIREMENT OF P55 GAG PRECURSOR FOR THE INCORPORATION OF THE VPR PRODUCT INTO HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 VIRIONS
Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 16)
Cohen EA, Yao XJ, Lavallee C, Jolicoeur P, Subramanian R, Ladha A
Overall, these results demonstrate a novel mechanism by which viral protein can be incorporated into viral particles. Identification of specific virion association motif(s) in the vpr protein may permit the development of chimeric molecules that can be specifically targeted into the mature HIV-1 virion to affect its structural organization or functional integrity.
17 PROTEIN-PROTEIN INTERACTIONS DURING ASSEMBLY OF HIV
Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 17)
Aldovini A, Jackson W, Young R
The results indicate that point mutations which affect sequences destined to become parts of MA p17, CA p24 or NC p7 all adversely affect Gag precursor interactions. These data suggest that multiple protein-protein interactions are involved between Gag precursors during virus assembly and provide a model to explain the molecular force behind budding.
18 THE p2 DOMAIN OF HIV-1 GAG REGULATES SEQUENTIAL PROCESSING BY THE PROTEASE AND IS REQUIRED FOR THE FULL INFECTIVITY OF VIRIONS
Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 18)
Pettit SC, Moody MD, Wehbie RS, Nantermet PV, Kaplan AH, Swanstrom R
HIV-1 virions deleted in the p2 domain of Gag had reduced infectivity despite the production of the processed final products of Gag. These results suggest that the p2 domain of HIV-1 Gag regulates sequential processing of the Gag precursor and that the presence of p2 is important for the formation of fully infectious virions.
19 HIV-1 Vpr is a nuclear protein that is incorporated into virions through the Gag p6 protein
Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 19)
Landau N1,2, Connor R1, Paxton W1, Ebright M1, Choe S1
We have also localized the tagged-Vpr cells by immunofluorescence. The results showed that Vpr is a nuclear protein. We are currently localizing the amino acids that determine nuclear localization using the mutated tagged Vpr vectors.
20 THE ACTIVATION DOMAIN OF HIV TAT PROTEINS SPECIFICALLY BINDS TO A CELLULAR PROTEIN KINASE
Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 20)
Herrmann CH, Rhim H, Echetebu CO, Rice AP
Our results suggest that a cellular serine/threonine kinase may act as a mediator of Tat function. We are currently purifying this kinase and further characterizing its biochemical properties.
Session 10—Seroepidemiology and HIV Incidence in U.S. Heterosexual Men and Women; Maternal and Fetal Risk; Tuberculosis
21 THE SEROEPIDEMIOLOGY OF HUMAN IMMUNODEFICIENCY VIRUS IN THE UNITED STATES HOUSEHOLD POPULATION: NHANES III, 1988-1991
Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 21)
McQuillan GM, Khare M, Ezzati TM, Schable CA, Murphy RS
The estimate does not include individuals who may be at higher risk of infection such as prisoners, the homeless or hospitalized patients. Because of higher non-response in young males these data provide a conservative estimate of HIV infection in the general household population.
22 BACKCALCULATION MODELS OF AGE-SPECIFIC HIV INCIDENCE
Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 22)
Rosenberg PS, Biggar RJ, Goedert JJ
Quantitative estimates were sensitive to the assumed incubation distribution, but the trend towards younger age at infection was a robust feature of the analysis.
23 INCREASING INCIDENCE OF HIV INFECTION AMONG U.S. WOMEN: ESTIMATES USING β2-MICROGLOBULIN IN AN HIV PREVALENCE STUDY, 1988-1991
Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 23)
Jansen R, Satten G, Petersen L
Among women, the prevalence of recent HIV infection increased from 1988 through 1991. The incidence of HIV infection may now be higher among women than among men seeking medical care at some U.S. hospitals.
24 ELEVATED HIV PREVALENCE IN FEMALE ADOLESCENT STD CLINIC PATIENTS
Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 24)
Heffernan R, Chiasson MA, Ewing W
HIV prevalence among adolescents in this clinic population is high, particularly among females, who face increased risk associated with drug use, trading sex, having an HIV+ sex partner and history of lesion STD.
25 HIV SEROINCIDENCE AMONG MALES ATTENDING SEXUALLY TRANSMITTED DISEASE CLINICS IN LOS ANGELES COUNTY
Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 25)
Ford WL, Andersen JD, Weber MD, Cheng FK, Kerndt PR
Seroincidence based on self- report suggests that sexual transmission is an important source of new HIV infections among males in STD clinics in Los Angeles County. Seroincidence among gay/bisexual males was higher than expected. Risk reduction intervention programs for patients attending STD clinics need to be reevaluated and strengthened.