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.
Publication types
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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 / chemistry
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AIDS Vaccines / immunology
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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 / genetics
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Antibody Affinity / immunology
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B-Lymphocytes / cytology
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B-Lymphocytes / immunology
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B-Lymphocytes / metabolism
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Binding Sites / immunology
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CD4 Antigens / immunology
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CD4 Antigens / metabolism
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Cell Lineage
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Complementarity Determining Regions / chemistry
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Complementarity Determining Regions / genetics
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Complementarity Determining Regions / immunology
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Epitope Mapping
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Epitopes, B-Lymphocyte / chemistry
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Epitopes, B-Lymphocyte / immunology
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Evolution, Molecular
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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 gp160 / chemistry*
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HIV Envelope Protein gp160 / immunology*
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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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Humans
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Models, Molecular
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Molecular Sequence Data
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Neutralization Tests
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Protein Structure, Tertiary
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Somatic Hypermutation, Immunoglobulin / genetics
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, B-Lymphocyte
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HIV Antibodies
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HIV Envelope Protein gp160