Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors

Tongqing Zhou; Rebecca M Lynch; Lei Chen; Priyamvada Acharya; Xueling Wu; Nicole A Doria-Rose; M Gordon Joyce; Daniel Lingwood; Cinque Soto; Robert T Bailer; Michael J Ernandes; Rui Kong; Nancy S Longo; Mark K Louder; Krisha McKee; Sijy O'Dell; Stephen D Schmidt; Lillian Tran; Zhongjia Yang; Aliaksandr Druz; Timothy S Luongo; Stephanie Moquin; Sanjay Srivatsan; Yongping Yang; Baoshan Zhang; Anqi Zheng; Marie Pancera; Tatsiana Kirys; Ivelin S Georgiev; Tatyana Gindin; Hung-Pin Peng; An-Suei Yang; NISC Comparative Sequencing Program; James C Mullikin; Matthew D Gray; Leonidas Stamatatos; Dennis R Burton; Wayne C Koff; Myron S Cohen; Barton F Haynes; Joseph P Casazza; Mark Connors; Davide Corti; Antonio Lanzavecchia; Quentin J Sattentau; Robin A Weiss; Anthony P West Jr; Pamela J Bjorkman; Johannes F Scheid; Michel C Nussenzweig; Lawrence Shapiro; John R Mascola; Peter D Kwong

doi:10.1016/j.cell.2015.05.007

Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors

Cell. 2015 Jun 4;161(6):1280-92. doi: 10.1016/j.cell.2015.05.007. Epub 2015 May 21.

Authors

Tongqing Zhou¹, Rebecca M Lynch¹, Lei Chen¹, Priyamvada Acharya¹, Xueling Wu¹, Nicole A Doria-Rose¹, M Gordon Joyce¹, Daniel Lingwood¹, Cinque Soto¹, Robert T Bailer¹, Michael J Ernandes¹, Rui Kong¹, Nancy S Longo¹, Mark K Louder¹, Krisha McKee¹, Sijy O'Dell¹, Stephen D Schmidt¹, Lillian Tran¹, Zhongjia Yang¹, Aliaksandr Druz¹, Timothy S Luongo¹, Stephanie Moquin¹, Sanjay Srivatsan¹, Yongping Yang¹, Baoshan Zhang¹, Anqi Zheng¹, Marie Pancera¹, Tatsiana Kirys¹, Ivelin S Georgiev¹, Tatyana Gindin², Hung-Pin Peng³, An-Suei Yang³; NISC Comparative Sequencing Program; James C Mullikin⁴, Matthew D Gray⁵, Leonidas Stamatatos⁵, Dennis R Burton⁶, Wayne C Koff⁷, Myron S Cohen⁸, Barton F Haynes⁹, Joseph P Casazza¹, Mark Connors¹⁰, Davide Corti¹¹, Antonio Lanzavecchia¹², Quentin J Sattentau¹³, Robin A Weiss¹⁴, Anthony P West Jr¹⁵, Pamela J Bjorkman¹⁶, Johannes F Scheid¹⁷, Michel C Nussenzweig¹⁸, Lawrence Shapiro¹⁹, John R Mascola²⁰, Peter D Kwong²¹

Affiliations

¹ Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
² Department of Biochemistry & Molecular Biophysics and Department of Systems Biology, Columbia University, New York, NY 10032, USA.
³ Genomics Research Center, Academia Sinica, and Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan 11221.
⁴ NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁶ 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.
⁷ International AIDS Vaccine Initiative, New York, NY 10038, USA.
⁸ Departments of Medicine, Epidemiology, Microbiology, and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁹ 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.
¹⁰ HIV-Specific Immunity Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
¹¹ 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.
¹² Institute for Research in Biomedicine, Università della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
¹³ Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RF, UK.
¹⁴ Division of Infection & Immunity, University College London, Gower Street, London WC1E 6BT, UK.
¹⁵ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
¹⁶ 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.
¹⁷ Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
¹⁸ Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA.
¹⁹ 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.
²⁰ Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: jmascola@nih.gov.
²¹ Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: pdkwong@nih.gov.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Antibodies, Neutralizing / chemistry*
Antibodies, Neutralizing / metabolism
Antibodies, Viral / chemistry*
Antibodies, Viral / metabolism
B-Lymphocytes / immunology
CD4 Antigens / metabolism
Complementarity Determining Regions
Epitopes, B-Lymphocyte
HIV Envelope Protein gp120 / chemistry*
HIV Envelope Protein gp120 / immunology
HIV Envelope Protein gp120 / metabolism*
HIV-1 / physiology*
Humans
Models, Molecular
Molecular Sequence Data
Sequence Alignment

Substances

Antibodies, Neutralizing
Antibodies, Viral
CD4 Antigens
Complementarity Determining Regions
Epitopes, B-Lymphocyte
HIV Envelope Protein gp120

Associated data

GENBANK/KP860914
GENBANK/KP860918
PDB/4RWY
PDB/4RX4
PDB/4YDI
PDB/4YDJ
PDB/4YDK
PDB/4YDL
PDB/4YE4
PDB/4YFL
SRA/SRP055520

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding