4.8 Article

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

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NATURE
卷 570, 期 7762, 页码 468-+

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NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-019-1250-z

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资金

  1. National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) [HIVRAD P01 AI100148]
  2. NIH [P50 GM082545-06]
  3. NIH Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) [1UM1 AI100663-01]
  4. Intramural Research Program of the NIAID
  5. NIGMS [R01GM130915]
  6. Gates CAVD grant [OPP1146996]
  7. NIH/NIAID [P01 AI138212]
  8. Robertson Fund of the Rockefeller University
  9. NSF GRFP
  10. EMBO fellowship
  11. HHMI Hanna Gray Fellowship
  12. Postdoctoral Enrichment Program from the Burroughs Welcome Fund
  13. National Center for Biomedical Glycomics [P41GM103490]
  14. NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZIAAI001213] Funding Source: NIH RePORTER

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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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