title: Genotypic correlates of susceptibility to HIV-1 attachment inhibitor BMS-626529, the active agent of the prodrug BMS-663068.
abstract: OBJECTIVE
  In an 8 day monotherapy study of subjects infected with HIV-1 (subtype B) (NCT01009814), BMS-626529 (an attachment inhibitor that binds to HIV-1 envelope glycoprotein gp120), administered as the prodrug BMS-663068, produced substantial declines in plasma HIV-1 RNA. However, large variability in susceptibility to BMS-626529 was noted and virus with low susceptibility was less likely to be suppressed by BMS-663068 administration. The current analysis sought to investigate the genotypic correlates of susceptibility to BMS-626529.
  
  
  METHODS
  In vitro selection experiments, evaluation of clinical samples of subtype B from the monotherapy study and evaluation of intrinsically resistant subtype AE viruses were conducted. Reverse genetics was used to identify key substitutions in envelope clones responsible for reduced susceptibility.
  
  
  RESULTS
  An M426L or S375M change were the major substitutions associated with reductions in susceptibility to BMS-626529 in baseline samples of subtype B viruses from the monotherapy study, with M434I and M475I contributing to a lesser extent. Class resistance in subtype AE viruses was mapped to 375H and 475I substitutions, found in the vast majority of these viruses. Analysis of multiple envelope clones from infected subjects showed higher intrasubject variability in susceptibility to BMS-626529 compared with other classes of entry inhibitors.
  
  
  CONCLUSIONS
  These data define key genotypic substitutions in HIV-1 gp120 that could confer phenotypic resistance to BMS-626529.
authors.affiliation: Bristol-Myers Squibb, Research and Development, Wallingford, CT, USA.
authors.forename: Nannan
authors.initials: N
authors.lastname: Zhou
authors.forename: Beata
authors.initials: B
authors.lastname: Nowicka-Sans
authors.forename: Brian
authors.initials: B
authors.lastname: McAuliffe
authors.forename: Neelanjana
authors.initials: N
authors.lastname: Ray
authors.forename: Betsy
authors.initials: B
authors.lastname: Eggers
authors.forename: Hua
authors.initials: H
authors.lastname: Fang
authors.forename: Li
authors.initials: L
authors.lastname: Fan
authors.forename: Matthew
authors.initials: M
authors.lastname: Healy
authors.forename: David R
authors.initials: DR
authors.lastname: Langley
authors.forename: Carey
authors.initials: C
authors.lastname: Hwang
authors.forename: Max
authors.initials: M
authors.lastname: Lataillade
authors.forename: George J
authors.initials: GJ
authors.lastname: Hanna
authors.forename: Mark
authors.initials: M
authors.lastname: Krystal
mesh_terms: D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D015699:HIV Envelope Protein gp120 / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D010755:Organophosphates / Q000494:pharmacology* / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011355:Prodrugs / Q000494:pharmacology* / Q000627:therapeutic use; D059386:Reverse Genetics; D017422:Sequence Analysis, DNA; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; C584152:BMS-626529; D015699:HIV Envelope Protein gp120; D010755:Organophosphates; D010879:Piperazines; D011355:Prodrugs; D014230:Triazoles; C514793:gp120 protein, Human immunodeficiency virus 1; C576364:fostemsavir
keywords: antiretroviral; envelope; glycoprotein; resistance; tropism