title: Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies.
abstract: Antibodies capable of neutralizing HIV-1 often target variable regions 1 and 2 (V1V2) of the HIV-1 envelope, but the mechanism of their elicitation has been unclear. Here we define the developmental pathway by which such antibodies are generated and acquire the requisite molecular characteristics for neutralization. Twelve somatically related neutralizing antibodies (CAP256-VRC26.01-12) were isolated from donor CAP256 (from the Centre for the AIDS Programme of Research in South Africa (CAPRISA)); each antibody contained the protruding tyrosine-sulphated, anionic antigen-binding loop (complementarity-determining region (CDR) H3) characteristic of this category of antibodies. Their unmutated ancestor emerged between weeks 30-38 post-infection with a 35-residue CDR H3, and neutralized the virus that superinfected this individual 15 weeks after initial infection. Improved neutralization breadth and potency occurred by week 59 with modest affinity maturation, and was preceded by extensive diversification of the virus population. HIV-1 V1V2-directed neutralizing antibodies can thus develop relatively rapidly through initial selection of B cells with a long CDR H3, and limited subsequent somatic hypermutation. These data provide important insights relevant to HIV-1 vaccine development.
authors.affiliation: 1] Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA [2].
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Doria-Rose
authors.affiliation: 1] Department of Biochemistry, Columbia University, New York, New York 10032, USA [2].
authors.forename: Chaim A
authors.initials: CA
authors.lastname: Schramm
authors.affiliation: 1] Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA [2].
authors.forename: Jason
authors.initials: J
authors.lastname: Gorman
authors.affiliation: 1] Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Johannesburg, 2131, South Africa [2] Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2050, South Africa [3] Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Congella, 4013, South Africa [4].
authors.forename: Penny L
authors.initials: PL
authors.lastname: Moore
authors.affiliation: 1] Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Johannesburg, 2131, South Africa [2] Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2050, South Africa.
authors.forename: Jinal N
authors.initials: JN
authors.lastname: Bhiman
authors.affiliation: Department of Chemical Engineering, University of Texas at Austin, Austin, Texas 78712, USA.
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: DeKosky
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ernandes
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Ivelin S
authors.initials: IS
authors.lastname: Georgiev
authors.affiliation: 1] Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA [2] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA [3] IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Pancera
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Staupe
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Han R
authors.initials: HR
authors.lastname: Altae-Tran
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Bailer
authors.affiliation: Torrey Pines Institute, San Diego, California 92037, USA.
authors.forename: Ema T
authors.initials: ET
authors.lastname: Crooks
authors.affiliation: Weill Medical College of Cornell University, New York, New York 10065, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Cupo
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Aliaksandr
authors.initials: A
authors.lastname: Druz
authors.affiliation: Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Congella, 4013, South Africa.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Garrett
authors.affiliation: Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas, USA.
authors.forename: Kam H
authors.initials: KH
authors.lastname: Hoi
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Kong
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Mark K
authors.initials: MK
authors.lastname: Louder
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Longo
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Krisha
authors.initials: K
authors.lastname: McKee
authors.affiliation: Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Johannesburg, 2131, South Africa.
authors.forename: Molati
authors.initials: M
authors.lastname: Nonyane
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Sijy
authors.initials: S
authors.lastname: O'Dell
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Roark
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Rudicell
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Schmidt
authors.affiliation: Institute of Infectious Diseases and Molecular Medicine, Division of Medical Virology, University of Cape Town and NHLS, Cape Town 7701, South Africa.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sheward
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Cinque
authors.initials: C
authors.lastname: Soto
authors.affiliation: 1] Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Johannesburg, 2131, South Africa [2] Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2050, South Africa.
authors.forename: Constantinos Kurt
authors.initials: CK
authors.lastname: Wibmer
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Biochemistry, Columbia University, New York, New York 10032, USA.
authors.forename: Zhenhai
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: 1] NISC Comparative Sequencing program, National Institutes of Health, Bethesda, Maryland 20892, USA [2] NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Mullikin
authors.affiliation: Torrey Pines Institute, San Diego, California 92037, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Binley
authors.affiliation: Department of Medical Microbiology, Academic Medical Center, Amsterdam 1105 AZ, Netherlands.
authors.forename: Rogier W
authors.initials: RW
authors.lastname: Sanders
authors.affiliation: 1] Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA [2] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA [3] IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA [4] Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
authors.affiliation: Weill Medical College of Cornell University, New York, New York 10065, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
authors.affiliation: 1] Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA [2] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA [3] IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Ward
authors.affiliation: 1] Department of Chemical Engineering, University of Texas at Austin, Austin, Texas 78712, USA [2] Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas, USA [3] Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas 78712, USA.
authors.forename: George
authors.initials: G
authors.lastname: Georgiou
authors.affiliation: 1] Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Congella, 4013, South Africa [2] Institute of Infectious Diseases and Molecular Medicine, Division of Medical Virology, University of Cape Town and NHLS, Cape Town 7701, South Africa.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Williamson
authors.affiliation: 1] Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Congella, 4013, South Africa [2] Department of Epidemiology, Columbia University, New York, New York 10032, USA.
authors.forename: Salim S
authors.initials: SS
authors.lastname: Abdool Karim
authors.affiliation: 1] Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Johannesburg, 2131, South Africa [2] Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2050, South Africa [3] Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Congella, 4013, South Africa.
authors.forename: Lynn
authors.initials: L
authors.lastname: Morris
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.affiliation: 1] Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA [2] Department of Biochemistry, Columbia University, New York, New York 10032, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Shapiro
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
mesh_terms: D016915:AIDS Vaccines / Q000737:chemistry / Q000276:immunology; D000595:Amino Acid Sequence; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D000915:Antibody Affinity / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D001665:Binding Sites / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism; D019070:Cell Lineage; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D018604:Epitope Mapping; D018985:Epitopes, B-Lymphocyte / Q000737:chemistry / Q000276:immunology; D019143:Evolution, Molecular; D015483:HIV Antibodies / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D019302:HIV Envelope Protein gp160 / Q000737:chemistry* / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000737:chemistry / Q000276:immunology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D017434:Protein Structure, Tertiary; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D022801:Complementarity Determining Regions; D018985:Epitopes, B-Lymphocyte; D015483:HIV Antibodies; D019302:HIV Envelope Protein gp160