Extended Data Fig. 9: Model of HIV-1 Env activation to induce membrane fusion.

A hypothesis of how the cellular receptors CD4 and CCR5 trigger the HIV-1 Env trimer to induce membrane fusion and viral entry. Left, virus attaches to the target cell by gp120 (cyan) binding to CD4 (green). Helix collar (gp41), the four-helix collar gripping the N- and C termini of gp120. Right, immediate binding by CCR5 (red) prevents rapid dissociation between gp120 and CD4, stabilizes the CD4-induced conformational changes within the Env trimer and brings the trimer close to the cell membrane. Simultaneous binding of gp120 to both CD4 and CCR5 may require bending in the cell membrane. The fusion peptide (magenta) of gp41 (grey) flips out owing to intrinsic conformational dynamics, which enables the bending back of the N and C termini of gp120. This bending blocks the fusion peptide from resuming its original position in the trimer. The movements of the fusion peptide and gp120 termini effectively weaken the non-covalent association between the two subunits and may lead to partial or complete dissociation of gp120, as well as a series of refolding events in gp41 to adopt the pre-hairpin intermediate conformation (with the fusion peptides inserting into the target-cell membrane). Extended helix (gp41), three helices in the fusion-intermediate conformation of gp41.