Intracellular Neutralization of HIV Transcytosis across Tight Epithelial Barriers by Anti-HIV Envelope Protein dIgA or IgM

Abstract

Human immunodeficiency virus, generated during contact between HIV-infected cells and the apical surface of an epithelial cell, can cross a tight epithelial barrier by transcytosis. We show that transcytosis of primary HIV isolates is blocked by dimeric IgA or IgM against HIV envelope proteins. Neutralization occurs intracellularly within the apical recycling endosome, and immune complexes are specifically recycled to the mucosal surface. One epitope involved in neutralization is a conserved sequence of the gp41 HIV envelope protein subunit. Finally, transcytosis also occurs across functional human mucosal tissue in a process inhibited by a serosal internalization of IgM against the HIV envelope protein. These results suggest that induction of mucosal immunity to HIV envelope proteins may impair the transcytotic route of HIV mucosal transmission.

Intraepithelial Cell Neutralization of HIV-1 Replication by IgA

“…In addition to the conventional neutralization activity mentioned, human IgA Ab has also been shown to be able to act intracellularly to block HIV transcytosis from the apical to the basolateral side of epithelial cell monolayers, suggesting the potential to inhibit spread of HIV from mucosal epithelium to the lamina propria (16,24,33,35,36). The ability of IgA Ab to act in this manner has been referred to as "intracellular neutralization" (16).…”

“…Neutralizing Ab D47A (anti-gp120), stained green with FITC, was distributed through all three horizontal sections (apical and middle more than basal) with the most intensity in the middle section. As shown in the merged images, HIV gp160 and D47A IgA were prominently colocalized in the apical and especially the middle sections (orange to yellow), suggesting the principle site, perhaps in the apical recycling endosome (16,46), of interaction between IgA Ab and HIV protein. Both non-neutralizing D10A (anti-gp41) and irrelevant IgA (anti-measles hemagglutinin) showed no colocalization with HIV protein, suggesting little or no interaction with HIV protein even though both IgAs were transported efficiently to the apical side.…”

“…With respect to HIV, IgA (and IgM) Abs placed at either the apical or basolateral surface have been reported to block transcytosis of virus from the apical to the basolateral side in a tight epithelial cell monolayer (16,24,(33)(34)(35)(36). These findings suggest that in vivo HIV-specific IgA can both exclude HIV from mucosal epithelial cells and prevent transcytosing HIV from spreading to the lamina propria, where abundant T cells and macrophages are potential targets of infection.…”

“…Since IgA Ab is capable of intercepting HIV that is transcytosing epithelial cells in the apical to basolateral direction and redirecting virus to the apical surface (16), it was important to determine whether this phenomenon could account for the virus reduction by IgA that was observed in the experiments described above. Accordingly, D47A, D10A, or irrelevant IgA was placed in the basolateral chamber of polarized Vero cell monolayers as described above.…”

HIV-1-Specific Mucosal CD8+ Lymphocyte Responses in the Cervix of HIV-1-Resistant Prostitutes in Nairobi

“…The exact mechanism by which these mucosal CTL could function is not yet clear. HIV-1 can cross into the submucosa by transcytosis across a tight epithelial barrier, a process that can be inhibited by HIV-specific IgA (30). Furthermore, CD4 ϩ and CCR5 ϩ cell populations, which are susceptible to productive HIV-1 infection, are present in this region (31,32).…”