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Immunization expands B cells specific to HIV-1 V3 glycan in mice and macaques.

  • Author(s): Escolano, Amelia;
  • Gristick, Harry B;
  • Abernathy, Morgan E;
  • Merkenschlager, Julia;
  • Gautam, Rajeev;
  • Oliveira, Thiago Y;
  • Pai, Joy;
  • West, Anthony P;
  • Barnes, Christopher O;
  • Cohen, Alexander A;
  • Wang, Haoqing;
  • Golijanin, Jovana;
  • Yost, Daniel;
  • Keeffe, Jennifer R;
  • Wang, Zijun;
  • Zhao, Peng;
  • Yao, Kai-Hui;
  • Bauer, Jens;
  • Nogueira, Lilian;
  • Gao, Han;
  • Voll, Alisa V;
  • Montefiori, David C;
  • Seaman, Michael S;
  • Gazumyan, Anna;
  • Silva, Murillo;
  • McGuire, Andrew T;
  • Stamatatos, Leonidas;
  • Irvine, Darrell J;
  • Wells, Lance;
  • Martin, Malcolm A;
  • Bjorkman, Pamela J;
  • Nussenzweig, Michel C
  • et al.
Abstract

Broadly neutralizing monoclonal antibodies protect against infection with HIV-1 in animal models, suggesting that a vaccine that elicits these antibodies would be protective in humans. However, it has not yet been possible to induce adequate serological responses by vaccination. Here, to activate B cells that express precursors of broadly neutralizing antibodies within polyclonal repertoires, we developed an immunogen, RC1, that facilitates the recognition of the variable loop 3 (V3)-glycan patch on the envelope protein of HIV-1. RC1 conceals non-conserved immunodominant regions by the addition of glycans and/or multimerization on virus-like particles. Immunization of mice, rabbits and rhesus macaques with RC1 elicited serological responses that targeted the V3-glycan patch. Antibody cloning and cryo-electron microscopy structures of antibody-envelope complexes confirmed that immunization with RC1 expands clones of B cells that carry the anti-V3-glycan patch antibodies, which resemble precursors of human broadly neutralizing antibodies. Thus, RC1 may be a suitable priming immunogen for sequential vaccination strategies in the context of polyclonal repertoires.

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