HIV-1 infections with multiple founders associate with the development of neutralization breadth

PLoS Pathog. 2022 Mar 18;18(3):e1010369. doi: 10.1371/journal.ppat.1010369. eCollection 2022 Mar.

Abstract

Eliciting broadly neutralizing antibodies (bnAbs) is a cornerstone of HIV-1 vaccine strategies. Comparing HIV-1 envelope (env) sequences from the first weeks of infection to the breadth of antibody responses observed several years after infection can help define viral features critical to vaccine design. We investigated the relationship between HIV-1 env genetics and the development of neutralization breadth in 70 individuals enrolled in a prospective acute HIV-1 cohort. Half of the individuals who developed bnAbs were infected with multiple HIV-1 founder variants, whereas all individuals with limited neutralization breadth had been infected with single HIV-1 founders. Accordingly, at HIV-1 diagnosis, env diversity was significantly higher in participants who later developed bnAbs compared to those with limited breadth (p = 0.012). This association between founder multiplicity and the subsequent development of neutralization breadth was also observed in 56 placebo recipients in the RV144 vaccine efficacy trial. In addition, we found no evidence that neutralization breath was heritable when analyzing env sequences from the 126 participants. These results demonstrate that the presence of slightly different HIV-1 variants in acute infection could promote the induction of bnAbs, suggesting a novel vaccine strategy, whereby an initial immunization with a cocktail of minimally distant antigens would be able to initiate bnAb development towards breadth.

Publication types

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

MeSH terms

  • Antibodies, Neutralizing
  • Epitopes
  • HIV Antibodies
  • HIV-1* / genetics
  • Humans
  • Prospective Studies
  • env Gene Products, Human Immunodeficiency Virus / genetics

Substances

  • 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-18-2-0040] (J.A.A.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.