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Abstract
HIV fusion is mediated by conformational changes in HIV envelope glycoprotein (Env)
that involves assembly of two heptad repeats (N- and C-HR) in the gp41 ectodomain
to form a six-helix bundle (6HB). Peptides corresponding to the N- and C-HR of gp41,
termed as fusion inhibitors, are potent inhibitors of HIV infection. However, HIV
rapidly develops resistance to such fusion inhibitors. To better understand mechanisms
of resistance that will aid development of new fusion inhibitors, we generated an
escape mutant virus to an N peptide inhibitor (N44). This virus, however, was also
equally resistant to T20 and other C peptides. This cross-resistance to fusion inhibitors
was surprising because T20 binds the N-HR, while N44 binds the C-HR. We show that
two point mutations, one each in the N-HR and C-HR were responsible for the resistance,
but structural modeling of these mutations indicate that the mutations would not directly
impair peptide binding. Further mechanistic studies of the resistant Env demonstrated
that the mutations conferred increased infection kinetics, greater sensitivity to
sCD4, enhanced syncytia formation, and enhanced exposure to CD4-induced epitopes.
In summary these findings indicate a novel resistance mechanism involving improved
receptor usage and faster entry kinetics. This indirect method of resistance is distinctively
different from previous reports of escape from C peptide inhibitors that involve reduced
peptide-binding affinity for the endogenous heptad repeat.