Figure 7: Conformational sampling of unliganded Env trimers.

(a) CD4 can bind the closed form of Env and allosterically induce an open conformation. In contrast, 17b can only bind to unliganded Env when the open conformation is transiently sampled, and by doing so it stabilizes this conformation. (b) Env trimers exist predominantly in the closed form in which the interactions between V1/V2 from each protomer are intact and V3 is occluded. Transient sampling of open conformations disrupts the inter-protomer interactions at the trimer apex. The trimers on higher tier (more neutralization-resistant) viruses are less likely to sample open conformations, thereby protecting conserved epitopes from NAbs. Tier 1 primary and cell line-adapted isolates sample the open conformation more often or for longer periods, which renders these viruses more vulnerable to neutralization. CD4-independent isolates (which are extremely neutralization sensitive) have evolved mutations that stabilize the open state, probably to facilitate co-receptor binding when CD4 is either present at low levels or entirely absent.