HIV-1 VACCINES. Priming a broadly neutralizing antibody response to HIV-1 using a germline-targeting immunogen

Science. 2015 Jul 10;349(6244):156-61. doi: 10.1126/science.aac5894. Epub 2015 Jun 18.

Abstract

A major goal of HIV-1 vaccine research is the design of immunogens capable of inducing broadly neutralizing antibodies (bnAbs) that bind to the viral envelope glycoprotein (Env). Poor binding of Env to unmutated precursors of bnAbs, including those of the VRC01 class, appears to be a major problem for bnAb induction. We engineered an immunogen that binds to VRC01-class bnAb precursors and immunized knock-in mice expressing germline-reverted VRC01 heavy chains. Induced antibodies showed characteristics of VRC01-class bnAbs, including a short CDRL3 (light-chain complementarity-determining region 3) and mutations that favored binding to near-native HIV-1 gp120 constructs. In contrast, native-like immunogens failed to activate VRC01-class precursors. The results suggest that rational epitope design can prime rare B cell precursors for affinity maturation to desired targets.

Publication types

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

MeSH terms

  • AIDS Vaccines / immunology*
  • Animals
  • Antibodies, Monoclonal / biosynthesis
  • Antibodies, Monoclonal / immunology*
  • Antibodies, Neutralizing / biosynthesis
  • Antibodies, Neutralizing / immunology*
  • Antibody Affinity
  • B-Lymphocytes / immunology
  • Broadly Neutralizing Antibodies
  • Complementarity Determining Regions / genetics
  • Complementarity Determining Regions / immunology
  • Epitopes / genetics
  • Epitopes / immunology
  • HIV Antibodies / biosynthesis
  • HIV Antibodies / immunology*
  • HIV Envelope Protein gp120 / genetics
  • HIV Envelope Protein gp120 / immunology*
  • HIV Infections / prevention & control*
  • HIV-1 / immunology*
  • Immunoglobulin Heavy Chains / genetics
  • Immunoglobulin Heavy Chains / immunology
  • Mice
  • Mice, Knockout

Substances

  • AIDS Vaccines
  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Broadly Neutralizing Antibodies
  • Complementarity Determining Regions
  • Epitopes
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • Immunoglobulin Heavy Chains
  • VRC01 monoclonal antibody
  • gp120 protein, Human immunodeficiency virus 1