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Title: Staged induction of HIV-1 glycan–dependent broadly neutralizing antibodies

A preventive HIV-1 vaccine should induce HIV-1–specific broadly neutralizing antibodies (bnAbs). However, bnAbs generally require high levels of somatic hypermutation (SHM) to acquire breadth, and current vaccine strategies have not been successful in inducing bnAbs. Because bnAbs directed against a glycosylated site adjacent to the third variable loop (V3) of the HIV-1 envelope protein require limited SHM, the V3-glycan epitope is an attractive vaccine target. By studying the cooperation among multiple V3-glycan B cell lineages and their coevolution with autologous virus throughout 5 years of infection, we identify key events in the ontogeny of a V3- glycan bnAb. Two autologous neutralizing antibody lineages selected for virus escape mutations and consequently allowed initiation and affinity maturation of a V3-glycan bnAb lineage. The nucleotide substitution required to initiate the bnAb lineage occurred at a low-probability site for activation-induced cytidine deaminase activity. Cooperation of B cell lineages and an improbable mutation critical for bnAb activity defined the necessary events leading to breadth in this V3- glycan bnAb lineage. These findings may, in part, explain why initiation of V3-glycan bnAbs is rare, and suggest an immunization strategy for inducing similar V3-glycan bnAbs.
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  1. Duke Univ. School of Medicine, Durham, NC (United States); Duke Human Vaccine Inst., Durham, NC (United States)
  2. Univ. of Pennsylvania, Philadelphia, PA (United States). Perelman School of Medicine
  3. Brigham and Women's Hospital (Harvard Medical School), Boston, MA (United States)
  4. Memorial Sloan Kettering Cancer Center, New York, NY (United States)
  5. Duke Human Vaccine Inst., Durham, NC (United States)
  6. Duke Human Vaccine Inst., Durham, NC (United States); Duke Univ. Schoole of Medicine, Durham, NC (United States)
  7. National Inst. of Health (NIH), Bethesda, MD (United States)
  8. National Inst. of Communicable Diseases, Johannesburg (South Africa)
  9. Univ. of Alabama, Burmingham, AL (United States)
  10. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  11. Kamuzu Central Hospital, Lilongwe (Malawi). Univ. of North Carolina Project
  12. Univ. of North Carolina, Chapel Hill, NC (United States)
  13. Boston Univ., MA (United States)
Publication Date:
Report Number(s):
Journal ID: ISSN 1946-6234
Grant/Contract Number:
Accepted Manuscript
Journal Name:
Science Translational Medicine
Additional Journal Information:
Journal Volume: 9; Journal Issue: 381; Journal ID: ISSN 1946-6234
Research Org:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org:
National Institutes of Health (NIH); USDOE
Country of Publication:
United States
60 APPLIED LIFE SCIENCES; Biological Science
OSTI Identifier: