A Neutralizing Antibody Recognizing PrimarilyN-Linked Glycan Targets the Silent Face of the HIV Envelope


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Abstract

SUMMARYVirtually the entire surface of the HIV-1-envelope trimer is recognized by neutralizing antibodies, except for a highly glycosylated region at the center of the “silent face” on the gp120 subunit. From an HIV-1-infected donor, #74, we identified antibody VRC-PG05, which neutralized 27% of HIV-1 strains. The crystal structure of the antigen-binding fragment of VRC-PG05 in complex with gp120 revealed an epitope comprised primarily of N-linked glycans from N262, N295, and N448 at the silent face center. Somatic hypermutation occurred preferentially at antibody residues that interacted with these glycans, suggesting somatic development of glycan recognition. Resistance to VRC-PG05 in donor #74 involved shifting of glycan-N448 to N446 or mutation of glycan-proximal residue E293. HIV-1 neutralization can thus be achieved at the silent face center by glycan-recognizing antibody; along with other known epitopes, the VRC-PG05 epitope completes coverage by neutralizing antibody of all major exposed regions of the prefusion closed trimer.Graphical AbstractHighlightsIdentified and defined crystal structure of antibody VRC-PG05 in complex with gp120VRC-PG05 epitope is at the center of the glycosylated silent face of HIV-1 gp120VRC-PG05 utilizes both glycopeptide and glycan-cluster mechanisms of recognitionVRC-PG05 completes neutralizing antibody coverage of the prefusion-closed Env trimerThe center of the “silent face” on the HIV-1 envelope is shielded by glycans and has been devoid of antibody recognition. Zhou et al. identify the antibody VRC-PG05, which binds a glycan-dominated epitope at the silent face center and completes antibody recognition of all major exposed regions of the envelope trimer.

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