title: The Nucleoside Analog BMS-986001 Shows Greater In Vitro Activity against HIV-2 than against HIV-1.
abstract: 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 (EC50s) ranging from 30 to 81 nM. In contrast, EC50s for group M and O isolates of HIV-1 ranged from 450 to 890 nM. Across all isolates tested, the average EC50 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-2ROD9 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.
authors.affiliation: Center for Emerging and Reemerging Infectious Diseases and Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington, USA smithra@u.washington.edu.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Smith
authors.affiliation: Center for Emerging and Reemerging Infectious Diseases and Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington, USA.
authors.forename: Dana N
authors.initials: DN
authors.lastname: Raugi
authors.affiliation: Center for Emerging and Reemerging Infectious Diseases and Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington, USA.
authors.forename: Vincent H
authors.initials: VH
authors.lastname: Wu
authors.affiliation: Center for Emerging and Reemerging Infectious Diseases and Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington, USA.
authors.forename: Sally S
authors.initials: SS
authors.lastname: Leong
authors.affiliation: Center for Emerging and Reemerging Infectious Diseases and Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington, USA.
authors.forename: Kate M
authors.initials: KM
authors.lastname: Parker
authors.affiliation: Center for Emerging and Reemerging Infectious Diseases and Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington, USA.
authors.forename: Mariah K
authors.initials: MK
authors.lastname: Oakes
authors.affiliation: Service des Maladies Infectieuses, CHNU de Fann, Dakar, Senegal.
authors.forename: Papa Salif
authors.initials: PS
authors.lastname: Sow
authors.affiliation: Service des Maladies Infectieuses, CHNU de Fann, Dakar, Senegal.
authors.forename: Selly
authors.initials: S
authors.lastname: Ba
authors.affiliation: Service des Maladies Infectieuses, CHNU de Fann, Dakar, Senegal.
authors.forename: Moussa
authors.initials: M
authors.lastname: Seydi
authors.affiliation: Center for Emerging and Reemerging Infectious Diseases and Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington, USA Department of Global Health, University of Washington, Seattle, Washington, USA.
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Gottlieb
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D015498:HIV-2 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D018119:Stavudine / Q000494:pharmacology; D013936:Thymidine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; C583040:BMS-986001; D018894:Reverse Transcriptase Inhibitors; D018119:Stavudine; C072416:reverse transcriptase, Human immunodeficiency virus 2; D054303:HIV Reverse Transcriptase; D013936:Thymidine