title: Ontogeny of recognition specificity and functionality for the broadly neutralizing anti-HIV antibody 4E10.
abstract: The process of antibody ontogeny typically improves affinity, on-rate, and thermostability, narrows polyspecificity, and rigidifies the combining site to the conformer optimal for binding from the broader ensemble accessible to the precursor. However, many broadly-neutralizing anti-HIV antibodies incorporate unusual structural elements and recognition specificities or properties that often lead to autoreactivity. The ontogeny of 4E10, an autoreactive antibody with unexpected combining site flexibility, was delineated through structural and biophysical comparisons of the mature antibody with multiple potential precursors. 4E10 gained affinity primarily by off-rate enhancement through a small number of mutations to a highly conserved recognition surface. Controverting the conventional paradigm, the combining site gained flexibility and autoreactivity during ontogeny, while losing thermostability, though polyspecificity was unaffected. Details of the recognition mechanism, including inferred global effects due to 4E10 binding, suggest that neutralization by 4E10 may involve mechanisms beyond simply binding, also requiring the ability of the antibody to induce conformational changes distant from its binding site. 4E10 is, therefore, unlikely to be re-elicited by conventional vaccination strategies.
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Kathryn A K
authors.initials: KA
authors.lastname: Finton
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Della
authors.initials: D
authors.lastname: Friend
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Jaffe
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Mesfin
authors.initials: M
authors.lastname: Gewe
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Holmes
authors.affiliation: Department of Genetics, Harvard University Medical School, and Division of Genetics, Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: H Benjamin
authors.initials: HB
authors.lastname: Larman
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stuart
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Kevin
authors.initials: K
authors.lastname: Larimore
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington, United States of America; Department of Medicine, University of Washington, Seattle, Washington, United States of America; Program in Immunology, Cancer Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Greenberg
authors.affiliation: Department of Genetics, Harvard University Medical School, and Division of Genetics, Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Elledge
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington, United States of America; Department of Global Health, University of Washington, Seattle, Washington, United States of America.
authors.forename: Leonidas
authors.initials: L
authors.lastname: Stamatatos
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Roland K
authors.initials: RK
authors.lastname: Strong
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D000918:Antibody Specificity; D000080908:Broadly Neutralizing Antibodies; D018360:Crystallography, X-Ray; D015483:HIV Antibodies / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D017386:Sequence Homology, Amino Acid; D020349:Surface Plasmon Resonance
chemical_list: C558559:4E10 monoclonal antibody; D000911:Antibodies, Monoclonal; D000080908:Broadly Neutralizing Antibodies; D015483:HIV Antibodies