Synergistic Inhibition of HIV-1 Envelope-Mediated Membrane Fusion by Inhibitors Targeting the N- and C-Terminal Heptad Repeats of gp41

摘要

The HIV-1 Envelope (Env) proteins that mediate membrane fusion represent a major target for the development of new AIDS therapies. Three classes of Env-mediated membrane fusion inhibitors have been described that specifically target the pre-hairpin intermediate conformation of gp41. Class 2 inhibitors bind to the C-terminal heptad repeat (C-HR) of gp41. The single example of a class 3 inhibitor targets the trimeric N-terminal heptad repeat (N-HR) of gp41 and has been postulated to sequestrate the N-HR of the pre-hairpin intermediate through the formation of fusion incompetent heterotrimers. In this paper we show that NCCG-gp41, a class 2 inhibitor, and N36^Mut(e,g), a class 3 inhibitor, synergistically inhibit Env-mediated membrane fusion for several representative HIV-1 strains (X4 and R5) in both a cell fusion assay (with membrane-bound CD4) and an Env-pseudotyped virus neutralization assay. The mechanistic, as well as potential therapeutic, implications of these observation for HIV-Env mediated membrane fusion are discussed.