Amino Acid Changes in the HIV-1 gp41 Membrane Proximal Region Control Virus Neutralization Sensitivity

EBioMedicine. 2016 Oct;12:196-207. doi: 10.1016/j.ebiom.2016.08.045. Epub 2016 Aug 31.

Abstract

Most HIV-1 vaccines elicit neutralizing antibodies that are active against highly sensitive (tier-1) viruses or rare cases of vaccine-matched neutralization-resistant (tier-2) viruses, but no vaccine has induced antibodies that can broadly neutralize heterologous tier-2 viruses. In this study, we isolated antibodies from an HIV-1-infected individual that targeted the gp41 membrane-proximal external region (MPER) that may have selected single-residue changes in viral variants in the MPER that resulted in neutralization sensitivity to antibodies targeting distal epitopes on the HIV-1 Env. Similarly, a single change in the MPER in a second virus from another infected-individual also conferred enhanced neutralization sensitivity. These gp41 single-residue changes thus transformed tier-2 viruses into tier-1 viruses that were sensitive to vaccine-elicited tier-1 neutralizing antibodies. These data demonstrate that Env amino acid changes within the MPER bnAb epitope of naturally-selected escape viruses can increase neutralization sensitivity to multiple types of neutralizing antibodies, and underscore the critical importance of the MPER for maintaining the integrity of the tier-2 HIV-1 trimer.

MeSH terms

  • AIDS Vaccines / genetics
  • AIDS Vaccines / immunology
  • Amino Acid Sequence
  • Amino Acid Substitution*
  • Animals
  • Antibodies, Blocking / immunology
  • Antibodies, Neutralizing / genetics
  • Antibodies, Neutralizing / immunology*
  • Antigenic Variation
  • Disease Models, Animal
  • Gene Expression
  • HIV Antibodies / genetics
  • HIV Antibodies / immunology*
  • HIV Envelope Protein gp120 / genetics
  • HIV Envelope Protein gp120 / immunology
  • HIV Envelope Protein gp41 / chemistry
  • HIV Envelope Protein gp41 / genetics*
  • HIV Envelope Protein gp41 / immunology*
  • HIV Infections / immunology
  • HIV Infections / prevention & control
  • HIV Infections / virology
  • HIV-1 / genetics*
  • HIV-1 / immunology*
  • Humans
  • Immunization
  • Macaca mulatta
  • Mutation
  • Neutralization Tests
  • Protein Interaction Domains and Motifs / genetics*
  • Protein Interaction Domains and Motifs / immunology*

Substances

  • AIDS Vaccines
  • Antibodies, Blocking
  • Antibodies, Neutralizing
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • HIV Envelope Protein gp41