Genotypic correlates of susceptibility to HIV-1 attachment inhibitor BMS-626529, the active agent of the prodrug BMS-663068

摘要

Objectives: 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-626529was noted and virus with low susceptibilitywas 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 fromthemonotherapystudy, withM434I andM475I contributing to a lesserextent. Class resistance in subtype AEviruseswasmapped to 375Hand 475I substitutions, found in the vast majority of these viruses. Analysis ofmultiple envelope clones frominfected subjects showed higher intrasubject variability in susceptibility to BMS-626529 compared with other classes of entry inhibitors. Conclusions: These data define key genotypic substitutions inHIV-1 gp120 that could confer phenotypic resistance to BMS-626529.