Fig. 6: A model for the regulation of HIV-1 Env conformation by the membrane-proximal base.

The membrane-proximal base comprises the gp120 C-termini and the gp41 MPER and α9 helices from all three Env protomers; for clarity, each of the components of the membrane-proximal base illustrated in the figure is from a single protomer. We hypothesize that an assemblage of these structural elements maintains the pretriggered (State-1) conformation of the Env ectodomain. In Env-expressing cells, cleavage of the gp160 Env precursor by the host furin protease frees the gp120 C-terminus to participate in the formation of the membrane-proximal base; this accounts for the dependence of the pretriggered (State-1) Env conformation on proteolytic maturation^22,23,24,25. Either spontaneously or as a result of receptor binding during virus entry, the pretriggered Env on virions can assume asymmetric conformations^7,8,9,10. If the pretriggered Env trimer is symmetric and the default intermediate conformation corresponds to that of the Tri FPPR Envs, the transition between these states would involve opening two of the interprotomer angles to greater than 120° and closing one interprotomer angle to less than 120°. In the Env protomers flanking the larger (>120°) opening angles, two conformational changes are proposed: 1) In one of the protomers (green), the gp41 HR1_N region transforms from a non-helical, as-yet-uncharacterized State-1 conformation to a helix; and 2) In the other protomer (blue), decreases in the structural order of the MPER allow the associated α9 helix to tilt and thereby stabilize the HR1_N helix on the adjacent protomer. In one of the gp41 subunits (red) flanking the smaller opening angle (<120°), the α9 helix is associated with a more ordered MPER. Without the interaction afforded by the tilting of this α9 helix, the HR1_N region of the other gp41 subunit (blue) flanking the smaller opening angle assumes a loop configuration. In this model, during virus entry, the transition of the gp41 HR1_N region from a non-helical structure to a helix primes the formation of the long HR1_N-HR1_C helical coiled coil in the prehairpin intermediate. Next, the interaction of the HR2 gp41 helix with the HR1 coiled coil forms the six-helix bundle, which mediates the fusion of the viral membrane (with the transmembrane (TM) anchor) and the target cell membrane (with the fusion peptide (FP)). For the prehairpin intermediate and fusion-active (six-helix bundle) conformations, only one Env protomer is depicted.