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

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-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 375 H and 475I substitutions, found in the vast majority of these viruses. Analysis of multiple envelope clones from infected subjects showed higher intra-subject 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.