D-102 The potency of broadly neutralizing antibodies directly relates to their ability to recognize the closed pre-fusion form of HIV Env

Abstract

Envelope glycoprotein (Env) trimers, the primary antigenic feature on the surface of the HIV-1 virus, are of key importance to vaccine design. Many highly potent and broadly reactive neutralizing antibodies (bNAbs) to Env are now known, some of which can counter >90% of circulating HIV-1 isolates. The structures of some bNAb-Env antigen complexes have been solved, but how bNAbs interact with Env trimers is largely unknown. Here we use Hydrogen/Deuterium exchange to examine the interactions between several bNAbs and soluble KNH1144 and BG505 SOSIP.664 trimers that closely mimic the pre-fusion “Closed” form of the native Env trimer. Highly potent bNAbs have only localized effects on the structure of the SOSIP.664 trimers. In contrast, complexes of trimers with more weakly neutralizing antibodies bound reveal global structural changes. We hypothesize that they preferentially recognize a more “Open” conformation of the trimer. Taken together with data on the kinetics of antibody binding, our results suggest that weakly neutralizing antibodies can only bind to their epitopes when the unliganded, Closed trimer temporarily opens via the transient weakening of interactions between the protomers. The rate and extent to which such opening motions occur may govern the global neutralization susceptibility of various HIV-1 isolates.