title: Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody.
abstract: Antibodies with ontogenies from VH1-2 or VH1-46-germline genes dominate the broadly neutralizing response against the CD4-binding site (CD4bs) on HIV-1. Here, we define with longitudinal sampling from time-of-infection the development of a VH1-46-derived antibody lineage that matured to neutralize 90% of HIV-1 isolates. Structures of lineage antibodies CH235 (week 41 from time-of-infection, 18% breadth), CH235.9 (week 152, 77%), and CH235.12 (week 323, 90%) demonstrated the maturing epitope to focus on the conformationally invariant portion of the CD4bs. Similarities between CH235 lineage and five unrelated CD4bs lineages in epitope focusing, length-of-time to develop breadth, and extraordinary level of somatic hypermutation suggested commonalities in maturation among all CD4bs antibodies. Fortunately, the required CH235-lineage hypermutation appeared substantially guided by the intrinsic mutability of the VH1-46 gene, which closely resembled VH1-2. We integrated our CH235-lineage findings with a second broadly neutralizing lineage and HIV-1 co-evolution to suggest a vaccination strategy for inducing both lineages.
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Mattia
authors.initials: M
authors.lastname: Bonsignori
authors.affiliation: Vaccine Research Center, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Tongqing
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Department of Systems Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Zizhang
authors.initials: Z
authors.lastname: Sheng
authors.affiliation: Vaccine Research Center, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.affiliation: Vaccine Research Center, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: M Gordon
authors.initials: MG
authors.lastname: Joyce
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Ozorowski
authors.affiliation: Vaccine Research Center, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Gwo-Yu
authors.initials: GY
authors.lastname: Chuang
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Department of Systems Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Chaim A
authors.initials: CA
authors.lastname: Schramm
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Wiehe
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: S Munir
authors.initials: SM
authors.lastname: Alam
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Bradley
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Morgan A
authors.initials: MA
authors.lastname: Gladden
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Kwan-Ki
authors.initials: KK
authors.lastname: Hwang
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Sheelah
authors.initials: S
authors.lastname: Iyengar
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Xiaozhi
authors.initials: X
authors.lastname: Lu
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Kan
authors.initials: K
authors.lastname: Luo
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Mangiapani
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Parks
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Hongshuo
authors.initials: H
authors.lastname: Song
authors.affiliation: Vaccine Research Center, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Priyamvada
authors.initials: P
authors.lastname: Acharya
authors.affiliation: Vaccine Research Center, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Bailer
authors.affiliation: Vaccine Research Center, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Allen
authors.initials: A
authors.lastname: Cao
authors.affiliation: Vaccine Research Center, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Aliaksandr
authors.initials: A
authors.lastname: Druz
authors.affiliation: Vaccine Research Center, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37232, USA; Department of Electrical Engineering and Computer Science, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Ivelin S
authors.initials: IS
authors.lastname: Georgiev
authors.affiliation: Vaccine Research Center, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Young D
authors.initials: YD
authors.lastname: Kwon
authors.affiliation: Vaccine Research Center, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Mark K
authors.initials: MK
authors.lastname: Louder
authors.affiliation: Vaccine Research Center, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Baoshan
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Vaccine Research Center, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Anqi
authors.initials: A
authors.lastname: Zheng
authors.affiliation: Vaccine Research Center, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Brenna J
authors.initials: BJ
authors.lastname: Hill
authors.affiliation: Vaccine Research Center, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Kong
authors.affiliation: Vaccine Research Center, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Cinque
authors.initials: C
authors.lastname: Soto
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 Research Center, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA; Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA; Department of Immunology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA; Department of Immunology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Moody
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: George M
authors.initials: GM
authors.lastname: Shaw
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Immunology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Garnett
authors.initials: G
authors.lastname: Kelsoe
authors.affiliation: Los Alamos National Laboratory, Los Alamos, NM 87544, USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Hraber
authors.affiliation: Los Alamos National Laboratory, Los Alamos, NM 87544, USA.
authors.forename: Bette T
authors.initials: BT
authors.lastname: Korber
authors.affiliation: Department of Pathology, Stanford School of Medicine, Palo Alto, CA 94305, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Boyd
authors.affiliation: Department of Pathology, Stanford School of Medicine, Palo Alto, CA 94305, USA.
authors.forename: Andrew Z
authors.initials: AZ
authors.lastname: Fire
authors.affiliation: Department of Microbiology, Boston University, Boston, MA 02118, USA; Department of Mathematics and Statistics, Boston University, Boston, MA 02118, USA.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Kepler
authors.affiliation: Vaccine Research Center, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Department of Systems Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Shapiro
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Ward
authors.affiliation: Vaccine Research Center, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Hua-Xin
authors.initials: HX
authors.lastname: Liao
authors.affiliation: Vaccine Research Center, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: pdkwong@nih.gov.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA; Department of Immunology, Duke University School of Medicine, Durham, NC 27710, USA; Duke Global Health Institute, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: barton.haynes@duke.edu.
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000595:Amino Acid Sequence; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D015483:HIV Antibodies / Q000737:chemistry / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015658:HIV Infections / Q000276:immunology* / Q000517:prevention & control; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016415:Sequence Alignment
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; C514793:gp120 protein, Human immunodeficiency virus 1