title: Comprehensive antigenic map of a cleaved soluble HIV-1 envelope trimer.
abstract: The trimeric envelope (Env) spike is the focus of vaccine design efforts aimed at generating broadly neutralizing antibodies (bNAbs) to protect against HIV-1 infection. Three recent developments have facilitated a thorough investigation of the antigenic structure of the Env trimer: 1) the isolation of many bNAbs against multiple different epitopes; 2) the generation of a soluble trimer mimic, BG505 SOSIP.664 gp140, that expresses most bNAb epitopes; 3) facile binding assays involving the oriented immobilization of tagged trimers. Using these tools, we generated an antigenic map of the trimer by antibody cross-competition. Our analysis delineates three well-defined epitope clusters (CD4 binding site, quaternary V1V2 and Asn332-centered oligomannose patch) and new epitopes at the gp120-gp41 interface. It also identifies the relationships among these clusters. In addition to epitope overlap, we defined three more ways in which antibodies can cross-compete: steric competition from binding to proximal but non-overlapping epitopes (e.g., PGT151 inhibition of 8ANC195 binding); allosteric inhibition (e.g., PGT145 inhibition of 1NC9, 8ANC195, PGT151 and CD4 binding); and competition by reorientation of glycans (e.g., PGT135 inhibition of CD4bs bNAbs, and CD4bs bNAb inhibition of 8ANC195). We further demonstrate that bNAb binding can be complex, often affecting several other areas of the trimer surface beyond the epitope. This extensive analysis of the antigenic structure and the epitope interrelationships of the Env trimer should aid in design of both bNAb-based therapies and vaccines intended to induce bNAbs.
authors: Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Ronald
authors: R
authors: Derking
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, IAVI Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, California, United States of America.
authors: Gabriel
authors: G
authors: Ozorowski
authors: Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Kwinten
authors: K
authors: Sliepen
authors: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York, United States of America.
authors: Anila
authors: A
authors: Yasmeen
authors: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York, United States of America.
authors: Albert
authors: A
authors: Cupo
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, IAVI Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, California, United States of America.
authors: Jonathan L
authors: JL
authors: Torres
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, IAVI Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, California, United States of America; Program in Molecular Structure and Function, The Hospital for Sick Children Research Institute and Departments of Biochemistry and Immunology, University of Toronto, Toronto, Ontario, Canada.
authors: Jean-Philippe
authors: JP
authors: Julien
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, IAVI Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, California, United States of America.
authors: Jeong Hyun
authors: JH
authors: Lee
authors: Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Thijs
authors: T
authors: van Montfort
authors: Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Steven W
authors: SW
authors: de Taeye
authors: HIV-Specific Immunity Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Mark
authors: M
authors: Connors
authors: Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, IAVI Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, California, United States of America; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America; Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, United States of America.
authors: Dennis R
authors: DR
authors: Burton
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, IAVI Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, California, United States of America; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors: Ian A
authors: IA
authors: Wilson
authors: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York, United States of America.
authors: Per-Johan
authors: PJ
authors: Klasse
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, IAVI Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, California, United States of America.
authors: Andrew B
authors: AB
authors: Ward
authors: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York, United States of America.
authors: John P
authors: JP
authors: Moore
authors: Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York, United States of America.
authors: Rogier W
authors: RW
authors: Sanders
mesh_terms: D057134:Antibodies, Neutralizing / Q000737:chemistry* / Q000276:immunology; D018604:Epitope Mapping; D000939:Epitopes / Q000737:chemistry* / Q000276:immunology; D015686:Gene Products, env / Q000737:chemistry* / Q000276:immunology; D015483:HIV Antibodies / Q000737:chemistry* / Q000276:immunology; D015488:HIV Antigens / Q000737:chemistry* / Q000276:immunology; D015497:HIV-1 / Q000737:chemistry* / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D000939:Epitopes; D015686:Gene Products, env; D015483:HIV Antibodies; D015488:HIV Antigens