Treatment options for individuals infected with human immunodeficiency virus type 2 (HIV-2) are restricted by the intrinsic resistance of the virus to nonnucleoside reverse transcriptase inhibitors (NNRTIs) and the reduced susceptibility of HIV-2 to several protease inhibitors (PIs) used in antiretroviral therapy (ART). In an effort to identify new antiretrovirals for HIV-2 treatment, we evaluated the in vitro activity of the investigational nucleoside analog BMS-986001 (2=,3=-didehydro-3=-deoxy-4=-ethynylthymidine; also known as censavudine, festinavir, OBP-601, 4=-ethynyl stavudine, or 4=-ethynyl-d4T). In single-cycle assays, BMS-986001 inhibited HIV-2 isolates from treatment-naive individuals, with 50% effective concentrations (EC 50 s) ranging from 30 to 81 nM. In contrast, EC 50 s for group M and O isolates of HIV-1 ranged from 450 to 890 nM. Across all isolates tested, the average EC 50 for HIV-2 was 9.5-fold lower than that for HIV-1 (64 ؎ 18 nM versus 610 ؎ 200 nM, respectively; mean ؎ standard deviation). BMS-986001 also exhibited full activity against HIV-2 variants whose genomes encoded the single amino acid changes K65R and Q151M in reverse transcriptase, whereas the M184V mutant was 15-fold more resistant to the drug than the parental HIV-2 ROD9 strain. Taken together, our findings show that BMS-986001 is an effective inhibitor of HIV-2 replication. To our knowledge, BMS-986001 is the first nucleoside analog that, when tested against a diverse collection of HIV-1 and HIV-2 isolates, exhibits more potent activity against HIV-2 than against HIV-1 in culture.
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