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Session 56 Poster Session Acute Infection: Resistance, Fitness, and Transmission Session Time: 4:30-6:30 pm Room 4E-F

376-M. Infectivity and in Vitro Replication of Sexually Transmitted Drug-Resistant HIV-1 Variants V. Simon*, J. Vanderhoeven, A. Hurley, H. Mizuno, N. Padte, A. Horowitz, and M. Markowitz Aaron Diamond AIDS Res. Ctr., Rockefeller Univ., New York, NY Background: It has been assumed that drug-resistant viruses are in general less replication-competent than wild types. However, these viruses are transmissible. To assess the properties of transmitted, drug-resistant HIV-1, we characterized primary isolates derived from subjects found to be newly infected with viruses displaying resistance to NRTI, NNRTI, PI, or multiple drug classes (MDR). Methods: Virus isolates were obtained using co-culture techniques. Recombinants containing PR and RT with or without the corresponding gag gene of selected isolates were constructed in a CCR5-tropic molecular backbone. Their infectivity, determined using reporter cell lines, was expressed relative to that of the recombinant clone NL4YU2. Replication kinetics were studied by infection of PBMCs, and infection efficiency rates were estimated by comparison of p24 antigen slopes. Results: 15 individuals with primary HIV-1 infection were identified within 90 days after sexual exposure (viral load median 5.8 log10 HIV-1 copies/mL). MDR (3), single class drug resistant (7), and susceptible (5) virus isolates displayed a broad range of infectivity (5%-200% compared to NL4YU2) and replication kinetics (slope 0.4-3.7). Interestingly, the infectivity of MDR- and PI-resistant isolates assessed in the absence of drugs was similar or higher than that of wild type viruses. Cloning of PR and RT from these isolates in NL4YU2 yielded in clones with lower infectivity. Additional cloning of the corresponding gag resulted in a partial restoration of infectivity, although not to levels comparable with either NL4YU2 or the parental isolate. Conclusions: Despite the presence of resistance to 1 or more drug classes, newly transmitted viral variants retain infectivity and replication capacity comparable to transmitted wild type viruses. However, when PR and RT are introduced into a neutral, CCR5-using background, the viral fitness of these resistant recombinants is reduced as compared to the parental isolates. These results suggest that co-evolution outside of pol is essential to maintain viral infectivity. Understanding these mechanisms will be critical to better assess the pathogenesis of mutant HIV-1 variants.

©2002 9th Conference on Retroviruses and Opportunistic Infections