HIV-1 gp41-specific monoclonal mucosal IgAs derived from highly exposed but IgG-seronegative individuals block HIV-1 epithelial transcytosis and neutralize CD4(+) cell infection: an IgA gene and functional analysis.
AIDS is mainly a sexually transmitted disease, and accordingly, mucosal tissues are the primary sites of natural human immunodeficiency virus type-1 (HIV-1) transmission. Mucosal immunoglobulin A (IgA) antibody specific for HIV-1 envelope gp41 subunit is one correlate of protection in individuals who are highly sexually exposed to HIV-1 but remain persistently IgG seronegative (HEPS). Understanding these peculiar IgAs at the gene and functional level is possible only with monoclonal IgAs. We have constructed a mucosal Fab IgA library from HEPS and have characterized a series of HIV-1 IgAs specific for gp41 that, in vitro, are transcytosis-blocking and infection-neutralizing. Characterization of their IgA genes shows that Fab specific for the gp41 membrane-proximal region harbors a long heavy-chain CDR3 loop (CDRH3) similar to the two broadly neutralizing IgG monoclonal antibodies, 2F5 and 4E10. Furthermore, the selected Fab IgA shows extensive somatic mutations that cluster in the CDR regions, indicating that affinity maturation due to an antigen-driven process had occurred in HEPS individuals, presumably upon multiple exposures to HIV. This analysis of HEPS monoclonal IgA gives a unique opportunity to correlate an antibody function (resistance to a pathogen in vivo) with an antibody gene. Such neutralizing monoclonal IgAs could be used in microbicide formulation.
Tudor
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Entrée Muqueuse du VIH et Immunité Muqueuse, (Mucosal Entry of HIV-1 and Mucosal Immunity), Departement de Biologie Cellulaire, (Cell Biology Department), Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.
Derrien
M
M
Diomede
L
L
Drillet
A-S
AS
Houimel
M
M
Moog
C
C
Reynes
J-M
JM
Lopalco
L
L
Bomsel
M
M
D000328:Adult; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D002584:Cervix Uteri / Q000276:immunology*; D017124:Conserved Sequence; D004781:Environmental Exposure; D005260:Female; D015322:Gene Rearrangement, B-Lymphocyte; D015483:HIV Antibodies / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D015700:HIV Envelope Protein gp41 / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control*; D018023:HIV Seronegativity / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology* / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007071:Immunoglobulin A, Secretory / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D007140:Immunoglobulin Fab Fragments / Q000235:genetics / Q000276:immunology; D008969:Molecular Sequence Data; D009092:Mucous Membrane / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology*; D019151:Peptide Library; D016415:Sequence Alignment; D017385:Sequence Homology; D012747:Sexual Partners; D014621:Vagina / Q000276:immunology*; D053586:Virus Internalization
D000911:Antibodies, Monoclonal; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41; C545841:HIV-1 envelope protein gp41 (649-684); D007071:Immunoglobulin A, Secretory; D007140:Immunoglobulin Fab Fragments; D010446:Peptide Fragments; D019151:Peptide Library