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Nat Struct Mol Biol. 2016 Jan;23(1):81-90. doi: 10.1038/nsmb.3144. Epub 2015 Dec 21.

Structures of HIV-1 Env V1V2 with broadly neutralizing antibodies reveal commonalities that enable vaccine design.

Author information

1
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Maryland, USA.
2
Department of Medicinal Chemistry, University of Washington, Seattle, Washington, USA.
3
Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA.
4
Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA.
5
NIH Intramural Sequencing Center (NISC), National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
6
Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
7
Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
8
Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa.
9
Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
10
Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Congella, South Africa.
11
Department of Biochemistry &Molecular Biophysics, Columbia University, New York, New York, USA.
12
Department of Systems Biology, Columbia University, New York, New York, USA.

Abstract

Broadly neutralizing antibodies (bNAbs) against HIV-1 Env V1V2 arise in multiple donors. However, atomic-level interactions had previously been determined only with antibodies from a single donor, thus making commonalities in recognition uncertain. Here we report the cocrystal structure of V1V2 with antibody CH03 from a second donor and model Env interactions of antibody CAP256-VRC26 from a third donor. These V1V2-directed bNAbs used strand-strand interactions between a protruding antibody loop and a V1V2 strand but differed in their N-glycan recognition. Ontogeny analysis indicated that protruding loops develop early, and glycan interactions mature over time. Altogether, the multidonor information suggested that V1V2-directed bNAbs form an 'extended class', for which we engineered ontogeny-specific antigens: Env trimers with chimeric V1V2s that interacted with inferred ancestor and intermediate antibodies. The ontogeny-based design of vaccine antigens described here may provide a general means for eliciting antibodies of a desired class.

PMID:
26689967
PMCID:
PMC4833398
DOI:
10.1038/nsmb.3144
[Indexed for MEDLINE]
Free PMC Article

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