title: Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing.
abstract: Antibody VRC01 is a human immunoglobulin that neutralizes about 90% of HIV-1 isolates. To understand how such broadly neutralizing antibodies develop, we used x-ray crystallography and 454 pyrosequencing to characterize additional VRC01-like antibodies from HIV-1-infected individuals. Crystal structures revealed a convergent mode of binding for diverse antibodies to the same CD4-binding-site epitope. A functional genomics analysis of expressed heavy and light chains revealed common pathways of antibody-heavy chain maturation, confined to the IGHV1-2*02 lineage, involving dozens of somatic changes, and capable of pairing with different light chains. Broadly neutralizing HIV-1 immunity associated with VRC01-like antibodies thus involves the evolution of antibodies to a highly affinity-matured state required to recognize an invariant viral structure, with lineages defined from thousands of sequences providing a genetic roadmap of their development.
authors.affiliation: Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Xueling
authors.initials: X
authors.lastname: Wu
authors.forename: Tongqing
authors.initials: T
authors.lastname: Zhou
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
authors.forename: Baoshan
authors.initials: B
authors.lastname: Zhang
authors.forename: Ivelin
authors.initials: I
authors.lastname: Georgiev
authors.forename: Charlene
authors.initials: C
authors.lastname: Wang
authors.forename: Xuejun
authors.initials: X
authors.lastname: Chen
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Longo
authors.forename: Mark
authors.initials: M
authors.lastname: Louder
authors.forename: Krisha
authors.initials: K
authors.lastname: McKee
authors.forename: Sijy
authors.initials: S
authors.lastname: O'Dell
authors.forename: Stephen
authors.initials: S
authors.lastname: Perfetto
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Schmidt
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: Lan
authors.initials: L
authors.lastname: Wu
authors.forename: Yongping
authors.initials: Y
authors.lastname: Yang
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Yang
authors.forename: Zhongjia
authors.initials: Z
authors.lastname: Yang
authors.forename: Zhenhai
authors.initials: Z
authors.lastname: Zhang
authors.forename: Mattia
authors.initials: M
authors.lastname: Bonsignori
authors.forename: John A
authors.initials: JA
authors.lastname: Crump
authors.forename: Saidi H
authors.initials: SH
authors.lastname: Kapiga
authors.forename: Noel E
authors.initials: NE
authors.lastname: Sam
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.forename: Melissa
authors.initials: M
authors.lastname: Simek
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Koff
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Doria-Rose
authors.forename: Mark
authors.initials: M
authors.lastname: Connors
authors.forename: James C
authors.initials: JC
authors.lastname: Mullikin
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Nabel
authors.forename: Mario
authors.initials: M
authors.lastname: Roederer
authors.forename: Lawrence
authors.initials: L
authors.lastname: Shapiro
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
mesh_terms: D016915:AIDS Vaccines; D000595:Amino Acid Sequence; D057134:Antibodies, Neutralizing / Q000737:chemistry* / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D000915:Antibody Affinity; D000918:Antibody Specificity; D001483:Base Sequence; D001665:Binding Sites; D001666:Binding Sites, Antibody; D015704:CD4 Antigens / Q000378:metabolism; D022801:Complementarity Determining Regions / Q000235:genetics; D018360:Crystallography, X-Ray; D000939:Epitopes; D019143:Evolution, Molecular; D050438:Genes, Immunoglobulin Heavy Chain; D015483:HIV Antibodies / Q000737:chemistry* / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000737:chemistry / Q000276:immunology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000276:immunology; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry / Q000276:immunology; D007144:Immunoglobulin J-Chains / Q000235:genetics; D007147:Immunoglobulin Light Chains / Q000737:chemistry / Q000276:immunology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D017422:Sequence Analysis, DNA
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D022801:Complementarity Determining Regions; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007140:Immunoglobulin Fab Fragments; D007143:Immunoglobulin Heavy Chains; D007144:Immunoglobulin J-Chains; D007147:Immunoglobulin Light Chains