![]() ![]() Here we report crystal structures of the V1/V2 domain of HIV-1 gp120 from strains CAP45 and ZM109 in complexes with the antigen-binding fragment (Fab) of PG9 at 2.19- and 1.80-Å resolution, respectively. Sera with these characteristics have been identified in a number of HIV-1 donor cohorts, and these quaternary-structure-preferring V1/V2-directed antibodies are among the most common broadly neutralizing responses in infected donors 13, 14.ĭespite extensive effort, V1/V2 had resisted atomic-level characterization. These antibodies all share specificity for an N-linked glycan at residue 160 in V1/V2 (HXB2 numbering) and show a preferential binding to the assembled viral spike over monomeric gp120 as well as a sensitivity to changes in V1/V2 and some V3 residues. Despite the diversity and glycosylation of V1/V2, a number of broadly neutralizing human antibodies have been identified that target this region, including the somatically related antibodies PG9 and PG16, which neutralize 70–80% of circulating HIV-1 isolates 10, antibodies CH01–CH04, which neutralize 40–50% 11, and antibodies PGT141–145, which neutralize 40–80% 12. The ~50–90 residues that comprise V1/V2 contain two of the most variable portions of the virus, and roughly 1 in 10 residues of V1/V2 are N-glycosylated. Localized by electron microscopy to a membrane-distal ‘cap’ 2– 5, which holds the spike in a neutralization-resistant conformation, V1/V2 is not essential for entry: its removal, however, renders the virus profoundly sensitive to antibody-mediated neutralization 6– 9. V1/V2 of the gp120 component of the viral spike is critical to this evasion. In addition to structurally defining V1/V2, the results thus identify a paradigm of antibody recognition for highly glycosylated antigens, which-with PG9-involves a site of vulnerability comprising just two glycans and a strand.Īs the sole viral target of neutralizing antibodies, the HIV-1 viral spike has evolved to evade antibody-mediated neutralization (reviewed in ref. The structures of V1/V2-directed antibodies CH04 and PGT145 indicate that they share a common mode of glycan penetration by extended anionic loops. PG9 recognition involves electrostatic, sequence-independent and glycan interactions: the latter account for over half the interactive surface but are of sufficiently weak affinity to avoid autoreactivity. ![]() V1/V2 forms a four-stranded β-sheet domain, in which sequence diversity and glycosylation are largely segregated to strand-connecting loops. Here we report the structure of V1/V2 in complex with PG9. Human antibodies such as PG9 nonetheless engage V1/V2 and neutralize 80% of HIV-1 isolates. Variable regions 1 and 2 (V1/V2) of human immunodeficiency virus-1 (HIV-1) gp120 envelope glycoprotein are critical for viral evasion of antibody neutralization, and are themselves protected by extraordinary sequence diversity and N-linked glycosylation. ![]()
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