Glycan Masking Focuses Immune Responses to the HIV-1 CD4-Binding Site and Enhances Elicitation of VRC01-Class Precursor Antibodies

Immunity. 2018 Aug 21;49(2):301-311.e5. doi: 10.1016/j.immuni.2018.07.005. Epub 2018 Jul 31.

Abstract

An important class of HIV-1 broadly neutralizing antibodies, termed the VRC01 class, targets the conserved CD4-binding site (CD4bs) of the envelope glycoprotein (Env). An engineered Env outer domain (OD) eOD-GT8 60-mer nanoparticle has been developed as a priming immunogen for eliciting VRC01-class precursors and is planned for clinical trials. However, a substantial portion of eOD-GT8-elicited antibodies target non-CD4bs epitopes, potentially limiting its efficacy. We introduced N-linked glycans into non-CD4bs surfaces of eOD-GT8 to mask irrelevant epitopes and evaluated these mutants in a mouse model that expressed diverse immunoglobulin heavy chains containing human IGHV1-2∗02, the germline VRC01 VH segment. Compared to the parental eOD-GT8, a mutant with five added glycans stimulated significantly higher proportions of CD4bs-specific serum responses and CD4bs-specific immunoglobulin G+ B cells including VRC01-class precursors. These results demonstrate that glycan masking can limit elicitation of off-target antibodies and focus immune responses to the CD4bs, a major target of HIV-1 vaccine design.

Keywords: CD4-binding site; HIV-1; VRC01; VRC01-class precursors; eOD-GT8; glycan masking; neutralizing antibody; single-cell sorting; transgenic mouse; vaccination.

Publication types

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

MeSH terms

  • AIDS Vaccines / immunology
  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Neutralizing / immunology*
  • Binding Sites, Antibody / immunology*
  • Broadly Neutralizing Antibodies
  • CD4 Antigens / immunology*
  • Cell Line
  • Female
  • Gene Knock-In Techniques
  • HIV Antibodies / immunology*
  • HIV Envelope Protein gp120 / immunology
  • HIV Infections / immunology
  • HIV Infections / prevention & control
  • HIV-1 / immunology*
  • Humans
  • Immunoglobulin Heavy Chains / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Polysaccharides / chemistry

Substances

  • AIDS Vaccines
  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Broadly Neutralizing Antibodies
  • CD4 Antigens
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • Immunoglobulin Heavy Chains
  • Polysaccharides
  • VRC01 monoclonal antibody