Structures of Natively-Glycosylated HIV-1 Envelope Trimers Define Antibody-Mediated Neutralization of HIV-1

Abstract

Broadly neutralizing antibodies (bNAbs) isolated from HIV-1 infected individuals inform vaccine design and are potential therapeutic agents. However, developing bNAbs with increased efficacy requires understanding how antibodies interact with the native oligomannose and complex-type N-glycan shield that hides most protein epitopes on HIV-1 envelope (Env). We present single-particle cryoEM structures of natively-glycosylated Env trimers complexed with newly identified bNAbs that target distinct epitopes on the surface of Env. A 3.3Å cryoEM structure of Env bound to SF12, an antibody that recognizes a glycan-dominated epitope on Env's silent face, revealed distinct N-glycan conformations across Env protomers, demonstrating intra-Env glycan heterogeneity. Insights from these antibody-Env complex structures have facilitated our understanding of bNAb-glycan interactions critical for their potential use in HIV-1 prevention, therapy, and vaccine development.