Ancestral sequences from an elite neutralizer proximal to the development of neutralization resistance as a potential source of HIV vaccine immunogens

PLoS One. 2019 Apr 10;14(4):e0213409. doi: 10.1371/journal.pone.0213409. eCollection 2019.

Abstract

A major challenge in HIV vaccine development is the identification of immunogens able to elicit broadly neutralizing antibodies (bNAbs). While remarkable progress has been made in the isolation and characterization of bNAbs, the epitopes they recognize appear to be poorly immunogenic. Thus, none of the candidate vaccines developed to date has induced satisfactory levels of neutralizing antibodies to the HIV envelope protein (Env). One approach to the problem of poor immunogenicity is to build vaccines based on envelope (env) genes retrieved from rare individuals termed elite neutralizers (ENs) who at one time possessed specific sequences that stimulated the formation of bNAbs. Env proteins selected from these individuals could possess uncommon, yet to be defined, structural features that enhance the immunogenicity of epitopes recognized by bNAbs. Here we describe the recovery of envs from an EN that developed unusually broad and potent bNAbs. As longitudinal specimens were not available, we combined plasma and provirus sequences acquired from a single time-point to infer a phylogenetic tree. Combining ancestral reconstruction data with virus neutralization data allowed us to sift through the myriad of virus quasi-species that evolved in this individual to identify envelope sequences from the nodes that appeared to define the transition from neutralization sensitive envs to the neutralization resistant envs that occur in EN plasma. Synthetic genes from these nodes were functional in infectivity assays and sensitive to neutralization by bNAbs, and may provide a novel source of immunogens for HIV vaccine development.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • AIDS Vaccines / blood
  • AIDS Vaccines / genetics*
  • AIDS Vaccines / immunology
  • Broadly Neutralizing Antibodies / genetics*
  • Broadly Neutralizing Antibodies / immunology
  • Epitopes / genetics
  • Epitopes / immunology
  • HIV / genetics
  • HIV / immunology*
  • HIV / pathogenicity
  • HIV Antibodies / blood
  • HIV Antibodies / genetics
  • HIV Antibodies / immunology
  • HIV Antigens / blood
  • HIV Antigens / genetics
  • HIV Antigens / immunology
  • HIV Infections / blood
  • HIV Infections / genetics
  • HIV Infections / immunology*
  • HIV Infections / virology
  • Humans
  • Immunogenicity, Vaccine / genetics
  • Neutralization Tests
  • Phylogeny
  • Proviruses / genetics
  • Proviruses / immunology
  • env Gene Products, Human Immunodeficiency Virus

Substances

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