Antibodies to a conformational epitope on gp41 neutralize HIV-1 by destabilizing the Env spike

Nat Commun. 2015 Sep 25;6:8167. doi: 10.1038/ncomms9167.

Abstract

The recent identification of three broadly neutralizing antibodies (bnAbs) against gp120-gp41 interface epitopes has expanded the targetable surface on the HIV-1 envelope glycoprotein (Env) trimer. By using biochemical, biophysical and computational methods, we map the previously unknown trimer epitopes of two related antibodies, 3BC315 and 3BC176. A cryo-EM reconstruction of a soluble Env trimer bound to 3BC315 Fab at 9.3 Å resolution reveals that the antibody binds between two gp41 protomers, and neutralizes the virus by accelerating trimer decay. In contrast, bnAb 35O22 binding to a partially overlapping quaternary epitope at the gp120-gp41 interface does not induce decay. A conserved gp41-proximal glycan at N88 was also shown to play a role in the binding kinetics of 3BC176 and 3BC315. Finally, our data suggest that the dynamic structure of the Env trimer influences exposure of bnAb epitopes.

Publication types

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

MeSH terms

  • Antibodies, Neutralizing / immunology*
  • Computer Simulation
  • Cryoelectron Microscopy
  • Crystallography, X-Ray
  • Epitope Mapping
  • Epitopes
  • HEK293 Cells
  • HIV Antibodies / immunology*
  • HIV Envelope Protein gp120 / immunology*
  • HIV Envelope Protein gp41 / immunology*
  • HIV-1 / immunology*
  • Humans
  • Immunoglobulin Fab Fragments / immunology
  • Immunoglobulin G / immunology
  • Models, Molecular
  • Protein Conformation

Substances

  • Antibodies, Neutralizing
  • Epitopes
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • HIV Envelope Protein gp41
  • Immunoglobulin Fab Fragments
  • Immunoglobulin G

Associated data

  • PDB/5AWN
  • PDB/5CCK