Journal
SCIENCE
Volume 366, Issue 6470, Pages 1216-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aax4380
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Funding
- National Institute of Allergy and Infectious Diseases (NIAID) [UM1 AI100663, UM1 AI144462]
- NIAID [R01 AI113867]
- Ragon Institute of MGH, MIT, and Harvard
- International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Consortium (NAC) and Center
- Collaboration for AIDS Vaccine Discovery
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Vaccine induction of broadly neutralizing antibodies (bnAbs) to HIV remains a major challenge. Germline-targeting immunogens hold promise for initiating the induction of certain bnAb classes; yet for most bnAbs, a strong dependence on antibody heavy chain complementarity-determining region 3 (HCDR3) is a major barrier. Exploiting ultradeep human antibody sequencing data, we identified a diverse set of potential antibody precursors for a bnAb with dominant HCDR3 contacts. We then developed HIV envelope trimer-based immunogens that primed responses from rare bnAb-precursor B cells in a mouse model and bound a range of potential bnAb-precursor human naive B cells in ex vivo screens. Our repertoire-guided germline-targeting approach provides a framework for priming the induction of many HIV bnAbs and could be applied to most HCDR3-dominant antibodies from other pathogens.
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