title: Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors.
abstract: The site on the HIV-1 gp120 glycoprotein that binds the CD4 receptor is recognized by broadly reactive antibodies, several of which neutralize over 90% of HIV-1 strains. To understand how antibodies achieve such neutralization, we isolated CD4-binding-site (CD4bs) antibodies and analyzed 16 co-crystal structures -8 determined here- of CD4bs antibodies from 14 donors. The 16 antibodies segregated by recognition mode and developmental ontogeny into two types: CDR H3-dominated and VH-gene-restricted. Both could achieve greater than 80% neutralization breadth, and both could develop in the same donor. Although paratope chemistries differed, all 16 gp120-CD4bs antibody complexes showed geometric similarity, with antibody-neutralization breadth correlating with antibody-angle of approach relative to the most effective antibody of each type. The repertoire for effective recognition of the CD4 supersite thus comprises antibodies with distinct paratopes arrayed about two optimal geometric orientations, one achieved by CDR H3 ontogenies and the other achieved by VH-gene-restricted ontogenies.
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Tongqing
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authors.lastname: Zhou
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Lynch
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Lei
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authors.lastname: Chen
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Priyamvada
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authors.lastname: Acharya
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Xueling
authors.initials: X
authors.lastname: Wu
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Doria-Rose
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: M Gordon
authors.initials: MG
authors.lastname: Joyce
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lingwood
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Cinque
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authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Bailer
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ernandes
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Rui
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authors.lastname: Kong
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Nancy S
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authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
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authors.initials: MK
authors.lastname: Louder
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Krisha
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authors.lastname: McKee
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Sijy
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authors.lastname: O'Dell
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
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authors.initials: SD
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authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
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authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
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authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Aliaksandr
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authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Luongo
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Stephanie
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authors.lastname: Moquin
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Sanjay
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authors.lastname: Srivatsan
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
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authors.initials: Y
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authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Baoshan
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Anqi
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authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
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authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
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authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
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authors.initials: IS
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authors.affiliation: Department of Biochemistry & Molecular Biophysics and Department of Systems Biology, Columbia University, New York, NY 10032, USA.
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authors.affiliation: Genomics Research Center, Academia Sinica, and Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan 11221.
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authors.initials: HP
authors.lastname: Peng
authors.affiliation: Genomics Research Center, Academia Sinica, and Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan 11221.
authors.forename: An-Suei
authors.initials: AS
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authors.affiliation: NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Mullikin
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
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authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
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authors.affiliation: Department of Immunology and Microbial Science, International AIDS Vaccine Initiative Neutralizing Antibody Center, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, MA 02142, USA.
authors.forename: Dennis R
authors.initials: DR
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authors.affiliation: International AIDS Vaccine Initiative, New York, NY 10038, USA.
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authors.initials: WC
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authors.affiliation: Departments of Medicine, Epidemiology, Microbiology, and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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authors.initials: MS
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authors.affiliation: Duke University Human Vaccine Institute, Departments of Medicine, Surgery, Pediatrics, and Immunology, Duke University School of Medicine and the Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery at Duke University, Durham, NC 27710, USA.
authors.forename: Barton F
authors.initials: BF
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authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
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authors.initials: JP
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authors.affiliation: HIV-Specific Immunity Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Mark
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authors.affiliation: Humabs BioMed SA, Via Mirasole 1, 6500 Bellinzona, Switzerland; Institute for Research in Biomedicine, Università della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
authors.forename: Davide
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authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
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authors.forename: Quentin J
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authors.affiliation: Division of Infection & Immunity, University College London, Gower Street, London WC1E 6BT, UK.
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authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
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authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125, USA.
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authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA; Department of Biochemistry & Molecular Biophysics and Department of Systems Biology, Columbia University, New York, NY 10032, USA.
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authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: jmascola@nih.gov.
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mesh_terms: D000595:Amino Acid Sequence; D057134:Antibodies, Neutralizing / Q000737:chemistry* / Q000378:metabolism; D000914:Antibodies, Viral / Q000737:chemistry* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology; D015704:CD4 Antigens / Q000378:metabolism; D022801:Complementarity Determining Regions; D018985:Epitopes, B-Lymphocyte; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016415:Sequence Alignment
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D015704:CD4 Antigens; D022801:Complementarity Determining Regions; D018985:Epitopes, B-Lymphocyte; D015699:HIV Envelope Protein gp120