Capturing glimpses of an elusive HIV gp41 prehairpin fusion intermediate

Abstract

Nuclear magnetic resonance (NMR) studies on an HIV gp41 construct reported by Lakomek and colleagues in this issue of Structure have revealed the conformational dynamics of a possible trimeric prehairpin fusion intermediate and its interactions with lipids. Two alternative fusion pathways are compared based on this work and a previous NMR structure of a monomeric lipid-bound gp41 ectodomain construct.

Figure 1. Two competing models of membrane-interacting pre-hairpin fusion intermediates of HIV gp41 based on solution NMR studies of various gp41 constructs in lipid micelles

The top path features pre-hairpin intermediates with trimeric NHR domains that may be interacting with lipids only transiently through their C-terminal end and IL domains according to Lakomek et al. (2014). The bottom path features pre-hairpin intermediates with dissociated NHR and CHR domains that both interact with opposing lipid bilayers according to Roche et al. (2014). Both pre-hairpin intermediate models fluctuate with ns dynamics and are in equilibrium (on a µs to ms dynamical scale) with early extended pre-fusion and late presumably lipid-mixing fusion intermediates. See text for abbreviations of gp41 sequence domain elements.