Structure of HIV-1 gp120 V1/V2 Domain With Broadly Neutralizing Antibody PG9

Nature. 2011 Nov 23;480(7377):336-43. doi: 10.1038/nature10696.

Abstract

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. Human antibodies such as PG9 nonetheless engage V1/V2 and neutralize 80% of HIV-1 isolates. Here we report the structure of V1/V2 in complex with PG9. V1/V2 forms a four-stranded β-sheet domain, in which sequence diversity and glycosylation are largely segregated to strand-connecting 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. The structures of V1/V2-directed antibodies CH04 and PGT145 indicate that they share a common mode of glycan penetration by extended anionic loops. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • AIDS Vaccines / chemistry
  • AIDS Vaccines / immunology
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Antibodies, Neutralizing / chemistry
  • Antibodies, Neutralizing / immunology*
  • Antibody Affinity / immunology
  • Antibody Specificity / immunology*
  • Antigen-Antibody Complex / chemistry
  • Antigen-Antibody Complex / immunology
  • Binding Sites, Antibody / immunology
  • Conserved Sequence
  • Crystallography, X-Ray
  • Epitopes / chemistry
  • Epitopes / immunology
  • Glycopeptides / chemistry
  • Glycopeptides / immunology
  • Glycosylation
  • HIV Antibodies / chemistry
  • HIV Antibodies / immunology*
  • HIV Envelope Protein gp120 / chemistry*
  • HIV Envelope Protein gp120 / immunology*
  • HIV-1 / chemistry*
  • HIV-1 / immunology*
  • Hydrogen Bonding
  • Immune Evasion
  • Models, Molecular
  • Molecular Sequence Data
  • Polysaccharides / chemistry
  • Polysaccharides / immunology
  • Protein Structure, Quaternary
  • Protein Structure, Tertiary

Substances

  • AIDS Vaccines
  • Antibodies, Neutralizing
  • Antigen-Antibody Complex
  • Epitopes
  • Glycopeptides
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • Polysaccharides

Associated data

  • PDB/3TCL
  • PDB/3U1S
  • PDB/3U2S
  • PDB/3U36
  • PDB/3U46
  • PDB/3U4B
  • PDB/3U4E