Structural characterization of a highly-potent V3-glycan broadly neutralizing antibody bound to natively-glycosylated HIV-1 envelope

Broadly neutralizing antibodies (bNAbs) isolated from HIV-1-infected individuals inform HIV-1 vaccine design efforts. 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). Here we present crystal structures, including a 3.8-angstrom X-ray free electron laser dataset, of natively glycosylated Env trimers complexed with BG18, the most potent V3/N332(gp120) glycan-targeting bNAb reported to date. Our structures show conserved contacts mediated by common D gene-encoded residues with the N332(gp120) glycan and the gp120 GDIR peptide motif, but a distinct Env-binding orientation relative to PGT121/10-1074 bNAbs. BG18's binding orientation provides additional contacts with N392(gp120) and N386(gp120) glycans near the V3-loop base and engages protein components of the V1-loop. The BG18-natively-glycosylated Env structures facilitate understanding of bNAb-glycan interactions critical for using V3/N332(gp120) bNAbs therapeutically and targeting their epitope for immunogen design.