title: Prevalence and gene characteristics of antibodies with cofactor-induced HIV-1 specificity.
abstract: The healthy immune repertoire contains a fraction of antibodies that bind to various biologically relevant cofactors, including heme. Interaction of heme with some antibodies results in induction of new antigen binding specificities and acquisition of binding polyreactivity. In vivo, extracellular heme is released as a result of hemolysis or tissue damage; hence the post-translational acquisition of novel antigen specificities might play an important role in the diversification of the immunoglobulin repertoire and host defense. Here, we demonstrate that seronegative immune repertoires contain antibodies that gain reactivity to HIV-1 gp120 upon exposure to heme. Furthermore, a panel of human recombinant antibodies was cloned from different B cell subpopulations, and the prevalence of antibodies with cofactor-induced specificity for gp120 was determined. Our data reveal that upon exposure to heme, ∼24% of antibodies acquired binding specificity for divergent strains of HIV-1 gp120. Sequence analyses reveal that heme-sensitive antibodies do not differ in their repertoire of variable region genes and in most of the molecular features of their antigen-binding sites from antibodies that do not change their antigen binding specificity. However, antibodies with cofactor-induced gp120 specificity possess significantly lower numbers of somatic mutations in their variable region genes. This study contributes to the understanding of the significance of cofactor-binding antibodies in immunoglobulin repertoires and of the influence that the tissue microenvironment might have in shaping adaptive immune responses.
authors.affiliation: From the Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, UMR S 1138, F-75006 Paris, France,; the Université Paris Descartes, UMR S 1138, F-75006 Paris, France,; INSERM U1138, F-75006 Paris, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Lecerf
authors.affiliation: the Deutsches Rheuma-Forschungszentrum, Institut der Leibniz-Gemeinschaft, 10117 Berlin, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Scheel
authors.affiliation: the Institute of Microbiology, Bulgarian Academy of Sciences, Sofia 1113, Bulgaria, and.
authors.forename: Anastas D
authors.initials: AD
authors.lastname: Pashov
authors.affiliation: From the Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, UMR S 1138, F-75006 Paris, France,; the Université Paris Descartes, UMR S 1138, F-75006 Paris, France,; INSERM U1138, F-75006 Paris, France.
authors.forename: Annaelle
authors.initials: A
authors.lastname: Jarossay
authors.affiliation: From the Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, UMR S 1138, F-75006 Paris, France,; the Université Paris Descartes, UMR S 1138, F-75006 Paris, France,; INSERM U1138, F-75006 Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Ohayon
authors.affiliation: From the Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, UMR S 1138, F-75006 Paris, France,; the Université Paris Descartes, UMR S 1138, F-75006 Paris, France,; INSERM U1138, F-75006 Paris, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Planchais
authors.affiliation: the Krebs Institute, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, United Kingdom.
authors.forename: Stephane
authors.initials: S
authors.lastname: Mesnage
authors.affiliation: the Deutsches Rheuma-Forschungszentrum, Institut der Leibniz-Gemeinschaft, 10117 Berlin, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Berek
authors.affiliation: From the Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, UMR S 1138, F-75006 Paris, France,; the Université Paris Descartes, UMR S 1138, F-75006 Paris, France,; INSERM U1138, F-75006 Paris, France.
authors.forename: Srinivas V
authors.initials: SV
authors.lastname: Kaveri
authors.affiliation: From the Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, UMR S 1138, F-75006 Paris, France,; the Université Paris Descartes, UMR S 1138, F-75006 Paris, France,; INSERM U1138, F-75006 Paris, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lacroix-Desmazes
authors.affiliation: From the Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, UMR S 1138, F-75006 Paris, France,; the Université Paris Descartes, UMR S 1138, F-75006 Paris, France,; INSERM U1138, F-75006 Paris, France,. Electronic address: jordan.dimitrov@crc.jussieu.fr.
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Dimitrov
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology*; D015483:HIV Antibodies / Q000235:genetics / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology
chemical_list: D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007135:Immunoglobulin Variable Region; C514793:gp120 protein, Human immunodeficiency virus 1
keywords: Antibody; Cloning; Cofactors; Heme; Human Immunodeficiency Virus (HIV); Immunoglobulin G (IgG); gp120