Secretory IgA specific for a conserved epitope on gp41 envelope glycoprotein inhibits epithelial transcytosis of HIV-1.
As one of the initial mucosal transmission pathways of HIV (HIV-1), epithelial cells translocate HIV-1 from apical to basolateral surface by nondegradative transcytosis. Transcytosis is initiated when HIV-1 envelope glycoproteins bind to the epithelial cell membrane. Here we show that the transmembrane gp41 subunit of the viral envelope binds to the epithelial glycosphingolipid galactosyl ceramide (Gal Cer), an alternative receptor for HIV-1, at a site involving the conserved ELDKWA epitope. Disrupting the raft organization of the Gal Cer-containing microdomains at the apical surface inhibited HIV-1 transcytosis. Immunological studies confirmed the critical role of the conserved ELDKWA hexapeptide in HIV-1 transcytosis. Mucosal IgA, but not IgG, from seropositive subjects targeted the conserved peptide, neutralized gp41 binding to Gal Cer, and blocked HIV-1 transcytosis. These results underscore the important role of secretory IgA in designing strategies for mucosal protection against HIV-1 infection.
Alfsen
A
A
Institut National de la Santé et de la Recherche Médicale, Unité 332, Institut Cochin de Genetique Moleculaire, Paris, France.
Iniguez
P
P
Bouguyon
E
E
Bomsel
M
M
D000328:Adult; D020816:Amino Acid Motifs / Q000276:immunology; D000918:Antibody Specificity; D001692:Biological Transport / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D002584:Cervix Uteri / Q000276:immunology; D003126:Colostrum / Q000276:immunology; D017124:Conserved Sequence / Q000276:immunology*; D003505:Cyclodextrins / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D000939:Epitopes / Q000276:immunology; D005260:Female; D005699:Galactosylceramides / Q000378:metabolism; D015483:HIV Antibodies / Q000502:physiology*; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D007071:Immunoglobulin A, Secretory / Q000502:physiology*; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D009092:Mucous Membrane / Q000276:immunology / Q000821:virology; D009500:Neutralization Tests; D014621:Vagina / Q000276:immunology; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D000939:Epitopes; D005699:Galactosylceramides; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D007071:Immunoglobulin A, Secretory; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin