Initiation of HIV neutralizing B cell lineages with sequential envelope immunizations

Nat Commun. 2017 Nov 23;8(1):1732. doi: 10.1038/s41467-017-01336-3.


A strategy for HIV-1 vaccine development is to define envelope (Env) evolution of broadly neutralizing antibodies (bnAbs) in infection and to recreate those events by vaccination. Here, we report host tolerance mechanisms that limit the development of CD4-binding site (CD4bs), HCDR3-binder bnAbs via sequential HIV-1 Env vaccination. Vaccine-induced macaque CD4bs antibodies neutralize 7% of HIV-1 strains, recognize open Env trimers, and accumulate relatively modest somatic mutations. In naive CD4bs, unmutated common ancestor knock-in mice Env+B cell clones develop anergy and partial deletion at the transitional to mature B cell stage, but become Env- upon receptor editing. In comparison with repetitive Env immunizations, sequential Env administration rescue anergic Env+ (non-edited) precursor B cells. Thus, stepwise immunization initiates CD4bs-bnAb responses, but immune tolerance mechanisms restrict their development, suggesting that sequential immunogen-based vaccine regimens will likely need to incorporate strategies to expand bnAb precursor pools.

Publication types

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

MeSH terms

  • AIDS Vaccines / immunology
  • Animals
  • Antibodies, Neutralizing / biosynthesis*
  • Antibodies, Neutralizing / chemistry
  • Antibodies, Neutralizing / genetics
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology*
  • Binding Sites, Antibody
  • CD4 Antigens / metabolism
  • Cell Lineage / immunology
  • Clonal Anergy
  • Female
  • Gene Knock-In Techniques
  • HIV Antibodies / biosynthesis*
  • HIV Antibodies / chemistry
  • HIV Antibodies / genetics
  • HIV-1 / immunology*
  • Humans
  • Immune Tolerance
  • Immunization / methods
  • Macaca mulatta
  • Male
  • Mice
  • Mice, Transgenic
  • Models, Molecular
  • env Gene Products, Human Immunodeficiency Virus / immunology*


  • AIDS Vaccines
  • Antibodies, Neutralizing
  • CD4 Antigens
  • HIV Antibodies
  • env Gene Products, Human Immunodeficiency Virus