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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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AIDS Vaccines
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Amino Acid Sequence
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Antibodies, Neutralizing / chemistry*
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Antibodies, Neutralizing / genetics
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Antibodies, Neutralizing / immunology*
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Antibodies, Neutralizing / isolation & purification
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Antibody Affinity
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Antibody Specificity
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Base Sequence
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Binding Sites
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Binding Sites, Antibody
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CD4 Antigens / metabolism
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Complementarity Determining Regions / genetics
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Crystallography, X-Ray
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Epitopes
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Evolution, Molecular*
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Genes, Immunoglobulin Heavy Chain
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HIV Antibodies / chemistry*
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HIV Antibodies / genetics
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HIV Antibodies / immunology*
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HIV Antibodies / isolation & purification
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HIV Envelope Protein gp120 / chemistry
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HIV Envelope Protein gp120 / immunology*
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HIV Envelope Protein gp120 / metabolism
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HIV Infections / immunology
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HIV-1 / chemistry
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HIV-1 / immunology*
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High-Throughput Nucleotide Sequencing
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Humans
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Immunoglobulin Fab Fragments / chemistry
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Immunoglobulin Fab Fragments / immunology
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Immunoglobulin Heavy Chains / chemistry
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Immunoglobulin Heavy Chains / immunology
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Immunoglobulin J-Chains / genetics
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Immunoglobulin Light Chains / chemistry
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Immunoglobulin Light Chains / immunology
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Models, Molecular
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Molecular Sequence Data
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Mutation
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Sequence Analysis, DNA
Substances
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AIDS Vaccines
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Antibodies, Neutralizing
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CD4 Antigens
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Complementarity Determining Regions
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Epitopes
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HIV Antibodies
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HIV Envelope Protein gp120
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Immunoglobulin Fab Fragments
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Immunoglobulin Heavy Chains
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Immunoglobulin J-Chains
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Immunoglobulin Light Chains