title: Minimally Mutated HIV-1 Broadly Neutralizing Antibodies to Guide Reductionist Vaccine Design.
abstract: An optimal HIV vaccine should induce broadly neutralizing antibodies (bnAbs) that neutralize diverse viral strains and subtypes. However, potent bnAbs develop in only a small fraction of HIV-infected individuals, all contain rare features such as extensive mutation, insertions, deletions, and/or long complementarity-determining regions, and some are polyreactive, casting doubt on whether bnAbs to HIV can be reliably induced by vaccination. We engineered two potent VRC01-class bnAbs that minimized rare features. According to a quantitative features frequency analysis, the set of features for one of these minimally mutated bnAbs compared favorably with all 68 HIV bnAbs analyzed and was similar to antibodies elicited by common vaccines. This same minimally mutated bnAb lacked polyreactivity in four different assays. We then divided the minimal mutations into spatial clusters and dissected the epitope components interacting with those clusters, by mutational and crystallographic analyses coupled with neutralization assays. Finally, by synthesizing available data, we developed a working-concept boosting strategy to select the mutation clusters in a logical order following a germline-targeting prime. We have thus developed potent HIV bnAbs that may be more tractable vaccine goals compared to existing bnAbs, and we have proposed a strategy to elicit them. This reductionist approach to vaccine design, guided by antibody and antigen structure, could be applied to design candidate vaccines for other HIV bnAbs or protective Abs against other pathogens.
authors: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.|IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Biochemistry, University of Washington, Seattle, Washington, United States of America.
authors: Joseph G
authors: JG
authors: Jardine
authors: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.|IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.|International AIDS Vaccine Initiative, New York, New York, United States of America.
authors: Devin
authors: D
authors: Sok
authors: IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Integrative Structural and Computational Biology, 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 Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.|IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.
authors: Bryan
authors: B
authors: Briney
authors: IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors: Anita
authors: A
authors: Sarkar
authors: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.|IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.
authors: Chi-Hui
authors: CH
authors: Liang
authors: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors: Erin A
authors: EA
authors: Scherer
authors: Department of Medicine, Section of Rheumatology, The Knapp Center for Lupus and Immunology Research, The University of Chicago, Chicago, Illinois, United States of America.
authors: Carole J
authors: CJ
authors: Henry Dunand
authors: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.|IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Biochemistry, University of Washington, Seattle, Washington, United States of America.
authors: Yumiko
authors: Y
authors: Adachi
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors: Devan
authors: D
authors: Diwanji
authors: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.|IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.
authors: Jessica
authors: 0000-0002-4070-5270
authors: J
authors: Hsueh
authors: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.|IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Biochemistry, University of Washington, Seattle, Washington, United States of America.
authors: Meaghan
authors: M
authors: Jones
authors: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.|IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Biochemistry, University of Washington, Seattle, Washington, United States of America.
authors: Oleksandr
authors: O
authors: Kalyuzhniy
authors: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.|IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.
authors: Michael
authors: M
authors: Kubitz
authors: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.|IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Biochemistry, University of Washington, Seattle, Washington, United States of America.
authors: Skye
authors: S
authors: Spencer
authors: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.|IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.
authors: Matthias
authors: M
authors: Pauthner
authors: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.|IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.
authors: Karen L
authors: KL
authors: Saye-Francisco
authors: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.|IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.
authors: Fabian
authors: F
authors: Sesterhenn
authors: Department of Medicine, Section of Rheumatology, The Knapp Center for Lupus and Immunology Research, The University of Chicago, Chicago, Illinois, United States of America.
authors: Patrick C
authors: PC
authors: Wilson
authors: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors: Denise M
authors: DM
authors: Galloway
authors: IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors: Robyn L
authors: RL
authors: Stanfield
authors: IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America.|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 Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.|IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, 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 Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.|IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Biochemistry, University of Washington, Seattle, Washington, United States of America.|Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, United States of America.
authors: William R
authors: WR
authors: Schief
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000595:Amino Acid Sequence; D057134:Antibodies, Neutralizing / Q000235:genetics / Q000276:immunology*; D015195:Drug Design; D015483:HIV Antibodies / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D057166:High-Throughput Screening Assays; D006801:Humans; D008958:Models, Molecular; D009154:Mutation
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies