Like other type 1 fusion machines, the HIV-1 envelope (Env) trimer transitions between prefusion, pre-hairpin intermediate and postfusion conformations to merge viral and host cell membranes during virus entry. In addition to utilizing conformational change for entry, the HIV-1 Env trimer also uses conformational change to evade the humoral immune response. Single molecule FRET measurements indicate that the Env trimer spontaneously (and reversibly) transitions between three prefusion states: a pre-triggered state 1, a preferred intermediate state 2, and an activated state 3 that can be stably induced by receptor/co-receptor binding. This talk summarizes recent data connecting smFRET-defined states with high-resolution structures and details how small molecules and antibodies can freeze select Env conformations to inhibit entry. In specific, we have recently solved the structure of the HIV-1 Env trimer with small molecule inhibitors, including BMS-626529, the prodrug version of which is currently in late stage clinical trials. This structure indicates BMS-626529 to recognize an induced binding pocket and to prevent Env from transitioning to state 3. Meanwhile, most broadly neutralizing antibodies appear to bind preferentially to states 1 or 2, although many can also bind to state 3. By contrast, poorly or non-neutralizing antibodies either do not recognize the Env trimer or only recognize state 3, not states 1 or 2. These insights into antibody recognition and Env conformation are now being applied to the development of vaccines aimed at eliciting immune responses capable of neutralizing the diverse neutralization-resistant isolates that typify HIV-1 transmission. Recent results indicate the N terminus of the fusion peptide to be exposed in state 2 and that focusing the immune response to this functionally critical site can elicit humoral immune responses in mice and non-human primates with ~30% HIV-1 neutralization breadth.
CROI Conference
