Immunization for HIV-1 Broadly Neutralizing Antibodies in Human Ig Knockin Mice

Cell. 2015 Jun 18;161(7):1505-15. doi: 10.1016/j.cell.2015.06.003.

Abstract

A subset of individuals infected with HIV-1 develops broadly neutralizing antibodies (bNAbs) that can prevent infection, but it has not yet been possible to elicit these antibodies by immunization. To systematically explore how immunization might be tailored to produce them, we generated mice expressing the predicted germline or mature heavy chains of a potent bNAb to the CD4 binding site (CD4bs) on the HIV-1 envelope glycoprotein (Env). Immunogens specifically designed to activate B cells bearing germline antibodies are required to initiate immune responses, but they do not elicit bNAbs. In contrast, native-like Env trimers fail to activate B cells expressing germline antibodies but elicit bNAbs by selecting for a restricted group of light chains bearing specific somatic mutations that enhance neutralizing activity. The data suggest that vaccination to elicit anti-HIV-1 antibodies will require immunization with a succession of related immunogens.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Neutralizing / genetics*
  • Antibodies, Viral / genetics*
  • Antigens, Viral
  • B-Lymphocytes / immunology
  • CD4 Antigens / metabolism
  • Gene Knock-In Techniques*
  • HIV Infections / immunology
  • HIV-1 / immunology*
  • Humans
  • Immunoglobulin Heavy Chains / genetics*
  • Mice
  • Mutation
  • Spleen / cytology
  • env Gene Products, Human Immunodeficiency Virus / metabolism

Substances

  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Antigens, Viral
  • CD4 Antigens
  • Immunoglobulin Heavy Chains
  • env Gene Products, Human Immunodeficiency Virus