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Sci Transl Med. 2017 Mar 15;9(381). pii: eaai7514. doi: 10.1126/scitranslmed.aai7514.

Staged induction of HIV-1 glycan-dependent broadly neutralizing antibodies.

Author information

1
Department of Medicine, Duke University School of Medicine, Duke University Medical Center, Durham, NC 27710, USA. mattia.bonsignori@dm.duke.edu btk@lanl.gov barton.haynes@dm.duke.edu.
2
Duke Human Vaccine Institute, Durham, NC 27710, USA.
3
Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
4
Laboratory of Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
5
Department of Medicine, Duke University School of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
6
Department of Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
7
Department of Surgery, Duke University School of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
8
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
9
Department of Immunology, Duke University School of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
10
National Institute for Communicable Diseases, Johannesburg 2131, South Africa.
11
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
12
Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
13
University of North Carolina Project, Kamuzu Central Hospital, Lilongwe, Malawi.
14
Departments of Medicine, Epidemiology, and Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
15
Department of Microbiology and Department of Mathematics and Statistics, Boston University, Boston, MA 02215, USA.
16
Department of Pediatrics, Duke University School of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
17
Los Alamos National Laboratory, Los Alamos, NM 87545, USA. mattia.bonsignori@dm.duke.edu btk@lanl.gov barton.haynes@dm.duke.edu.

Abstract

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.

PMID:
28298420
PMCID:
PMC5562350
DOI:
10.1126/scitranslmed.aai7514
[Indexed for MEDLINE]
Free PMC Article

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