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Abstract: Transmission of drug-resistant HIV has been widely documented. We generated tenofovir (TFV)- and emtricitabine (FTC)-resistant SHIV162P3 mutants that can be used to investigate the transmission efficiency of drug-resistant viruses and their impact on the efficacy of pre-exposure prophylaxis. Both SHIV162p3M184V and SHIV162p3K65R replicated in vitro at high titers. Drug resistance profiles were similar to those seen in HIV. Virus infectivity to virion particle ratios were 4- and 10-fold lower in SHIV162p3M184V and SHIV162p3K65R, compared to a concurrently generated WT SHIV162p3, respectively. Mucosal transmissibility studies using a repeat low-dose macaque model of rectal and vaginal transmission showed that both mutants were able to efficiently infect macaques only after the dose was increased to adjust for fitness reductions due to K65R and M184V. Our results in limited number of macaques suggest that the reduction in fitness due to M184V and K65R decreases virus transmissibility, and identify in vitro infectivity parameters that associate with mucosal transmissibility. [Copyright &y& Elsevier]

Abstract: Zidovudine (AZT) is a reverse transcriptase (RT) inhibitor widely used to treat persons infected with HIV-1 and HIV-2. Recent data on treated patients suggest differences in the antiviral activity of AZT between HIV-1 and HIV-2. We evaluated the antiviral activity of AZT on HIV-2 by using multiple approaches including in vitro selection experiments, analysis of growth kinetics with AZT, and phenotypic testing. A total of 5 wild-type (WT) HIV-2 viruses were used in the analysis. For comparison, 4 control WT HIV-1 strains and one HIV-1 mutant carrying the 215S mutation were evaluated in parallel. All 5 HIV-1 isolates acquired AZT resistance mutations after 3–6 passages with AZT or a 4- to 32-fold increase in AZT concentration. Among these viruses, the fastest selection of resistance was seen in HIV-1S215, which acquired S215Y (1-nucleotide change only) at passage 3 after only 17 days in culture. In contrast, none of the 5 HIV-2 viruses that naturally have S215 acquired S215Y/F or any other RT mutation during 10 passages with AZT (1025-fold increase in AZT concentration). In the presence of AZT + didanosine (ddI), 3 of the 5 HIV-1 isolates acquired AZT or ddI resistance mutations, while only ddI resistance mutations were seen in HIV-2 (4 of 5 isolates). All HIV-2 viruses replicated efficiently in high AZT concentrations and were about 200-fold less sensitive to AZT than HIV-1. In contrast, HIV-2 and HIV-1 were equally susceptible to ddI, a finding consistent with the selection of HIV-2 mutants with AZT + ddI. Our results demonstrate that the activity of AZT on HIV-2 is lower than previously thought, and emphasize the need for novel antiretroviral drugs specific for HIV-2. [Copyright &y& Elsevier]