Mucosal surfaces are the site of HIV transmission except for direct intravenous injection, and mucosal epithelial is therefore likely to e an important initial site of virus and host interaction. Furthermore, infectious HIV has been shown to be able to transcytose form the apical (luminal) to the basolateral (lamina propria) side of epithelial cells in vitro. Thus, immunity at mucosal surfaces could play a pivotal role in resisting HIV infection. Recent attention has focused on mucosal vaccine approaches for the prevention of HIV transmission. Since the major immune defense mediator at the mucosal surface is IgA, there is an urgent need for improved understanding of the function of IgA antibodies against HIV and other viruses. Secretory IgA at mucosal surfaces has been shown to inhibit viral infection through (s) immune exclusion, its traditional function, and other mechanisms. Particularly, the novel mechanisms recently identified by our group, including (b) intraepithelial cell neutralization of viral replication during IgA transepithelial transcytosis and (c) excretion of antigens from the basolateral (laminal propria) epithelia cell surface to the apical (luminal) surface in the form of IgA immune complexes, merit deeper investigation. Since infectious HIV virions may enter mucosal epithelial cells at the apical surface and be transcytosed to the basolateral surface prior to infecting target cells in the lamina propria, we believe that HIV-specific IgA antibodies may sere yet another function by (d) intercepting virions that are traversing the mucosal epithelium and thereby blocking the spread of virus. Our hypothesis is that HIV-specific IgA antibodies, primarily IgA, can counter HI infection of mucous membranes. The theme of this project interfaces closely with the significance of secretory antibodies in the outcome of gastrointestinal infection (Project 1 and Project 2) and respiratory infection (Project 4). The research also has significance for vaccine strategies against mucosal infection. Development of such vaccines is an integral part of Projects 1 and 2. Project 3 is dependent on Core B for multiple anti-HIV monoclonal antibodies.
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