Broad and potent neutralization of HIV-1 by a gp41-specific human antibody

Nature. 2012 Nov 15;491(7424):406-12. doi: 10.1038/nature11544. Epub 2012 Sep 18.

Abstract

Characterization of human monoclonal antibodies is providing considerable insight into mechanisms of broad HIV-1 neutralization. Here we report an HIV-1 gp41 membrane-proximal external region (MPER)-specific antibody, named 10E8, which neutralizes ∼98% of tested viruses. An analysis of sera from 78 healthy HIV-1-infected donors demonstrated that 27% contained MPER-specific antibodies and 8% contained 10E8-like specificities. In contrast to other neutralizing MPER antibodies, 10E8 did not bind phospholipids, was not autoreactive, and bound cell-surface envelope. The structure of 10E8 in complex with the complete MPER revealed a site of vulnerability comprising a narrow stretch of highly conserved gp41-hydrophobic residues and a critical arginine or lysine just before the transmembrane region. Analysis of resistant HIV-1 variants confirmed the importance of these residues for neutralization. The highly conserved MPER is a target of potent, non-self-reactive neutralizing antibodies, suggesting that HIV-1 vaccines should aim to induce antibodies to this region of HIV-1 envelope glycoprotein.

Publication types

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

MeSH terms

  • Amino Acid Substitution
  • Antibodies, Neutralizing / chemistry
  • Antibodies, Neutralizing / metabolism*
  • Antibody Specificity
  • Cells, Cultured
  • HEK293 Cells
  • HIV Antibodies / chemistry
  • HIV Antibodies / isolation & purification
  • HIV Antibodies / metabolism*
  • HIV Envelope Protein gp41 / chemistry
  • HIV Envelope Protein gp41 / immunology*
  • HIV-1 / physiology*
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Binding
  • Protein Structure, Tertiary

Substances

  • Antibodies, Neutralizing
  • HIV Antibodies
  • HIV Envelope Protein gp41

Associated data

  • GENBANK/JX645769
  • GENBANK/JX645770
  • PDB/4G6F