Altered Bystander Apoptosis Induction and Pathogenesis of Enfuvirtide-Resistant HIV Type 1 Env Mutants

In previous studies on mechanisms of HIV-1-mediated pathogenesis we showed that bystander apoptosis mediated by cell surface-expressed HIV-1 Env correlated with the fusogenic properties of the gp41 subunit of Env. A crucial step in HIV gp41-mediated fusion is the refolding of the protein into a six-helix bundle along the N- and C-terminal coiled-coil domains. These domains have been targeted by peptide inhibitors that inhibit gp41-mediated fusion. One of these inhibitors, enfuvirtide, is the first such drug approved for therapy. More recently, clinical data suggest that the beneficial effects of enfuvirtide extend beyond virus suppression and are associated with certain resistance mutations in gp41. In this study we characterized the bystander apoptosis-inducing potential of mutants associated with increased CD4 counts that arise during enfuvirtide therapy. Whereas all mutant clones were reduced in both cell-to-cell fusion activity and apoptosis induction there was limited effect on virus infection or replication. The viruses were found to have apoptosis-inducing activity in the order WT > V38M > V38A > G36D > V38E, which correlated with cell-to-cell fusion but not infection. Interestingly, the level of resistance as determined by the IC50 of enfuvirtide also correlated inversely with both cell fusion and apoptosis in that the most resistant Envs were the least fusogenic and pathogenic. This suggests the beneficial effects of enfuvirtide therapy beyond virus suppression may be mediated by selecting less pathogenic HIV isolates over time.