The breadth of HIV-1 neutralizing antibodies depends on the conservation of key sites in their epitopes

PLoS Comput Biol. 2019 Jun 6;15(6):e1007056. doi: 10.1371/journal.pcbi.1007056. eCollection 2019 Jun.

Abstract

Developing HIV-1 vaccines that trigger broadly neutralizing antibodies (bnAbs) is a priority as bnAbs are considered key to elicitation of a protective immune response. To investigate whether the breadth of a neutralizing antibody (nAb) depended on the conservation of its epitope among circulating viruses, we examined Antibody:Envelope (Ab:Env) interactions and worldwide Env diversity. We found that sites corresponding to bnAb epitopes were as variable as other accessible, non-hypervariable Env sites (p = 0.50, Mann-Whitney U-test) with no significant relationship between epitope conservation and neutralization breadth (Spearman's ρ = -0.44, adjusted p = 0.079). However, when accounting for key sites in the Ab:Env interaction, we showed that the broadest bnAbs targeted more conserved epitopes (Spearman's ρ = -0.70, adjusted p = 5.0e-5). Neutralization breadth did not stem from the overall conservation of Ab epitopes but depended instead on the conservation of key sites of the Ab:Env interaction, revealing a mechanistic basis for neutralization breadth that could be exploited for vaccine design.

Publication types

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

MeSH terms

  • AIDS Vaccines
  • Antibodies, Neutralizing* / genetics
  • Antibodies, Neutralizing* / immunology
  • Computational Biology
  • Conserved Sequence* / genetics
  • Conserved Sequence* / immunology
  • Epitopes / genetics
  • Epitopes / immunology
  • HIV Antibodies* / genetics
  • HIV Antibodies* / immunology
  • Molecular Dynamics Simulation
  • env Gene Products, Human Immunodeficiency Virus / genetics
  • env Gene Products, Human Immunodeficiency Virus / immunology

Substances

  • AIDS Vaccines
  • Antibodies, Neutralizing
  • Epitopes
  • HIV Antibodies
  • env Gene Products, Human Immunodeficiency Virus

Grants and funding

This work was supported by a cooperative agreement between The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of the Army [W81XWH-11-2-0174]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.