Immunity. 2019 Jun 18; 50(6):1513-1529.e9.

PubMed ID: 31126879

Broad and potent neutralizing antibodies recognize the silent face of the HIV envelope

Schoofs T, Barnes CO, Suh-Toma N, Golijanin J, Schommers P, Gruell H, West AP Jr, Bach F, Lee YE, Nogueira L, Georgiev IS, Bailer RT, Czartoski J, Mascola JR, Seaman MS, McElrath MJ, Doria-Rose NA, Klein F, Nussenzweig MC, Bjorkman PJ

Broadly neutralizing antibodies (bNAbs) against HIV-1 envelope (Env) inform vaccine design and are potential therapeutic agents. We identified SF12 and related bNAbs with up to 62% neutralization breadth from an HIV-infected donor. SF12 recognized a glycan-dominated epitope on Env's silent face and was potent against clade AE viruses, which are poorly covered by V3-glycan bNAbs. A 3.3Å cryo-EM structure of a SF12-Env trimer complex showed additional contacts to Env protein residues by SF12 compared with VRC-PG05, the only other known donor-derived silentface antibody, explaining SF12's increased neutralization breadth, potency, and resistance to Env mutation routes. Asymmetric binding of SF12 was associated with distinct N-glycan conformations across Env protomers, demonstrating intra-Env glycan heterogeneity. Administrating SF12 to HIV-1-infected humanized mice suppressed viremia and selected for viruses lacking the N448gp120 glycan. Effective bNAbs can therefore be raised against HIV-1 Env's silent face, suggesting their potential for HIV-1 prevention, therapy, and vaccine development.