Gastrointestinal associated lymphoid tissue (GALT) contains most of the body's lymphocytes, and therefore constitutes an immense compartment for persistent HIV-1 infection. Moreover, the GALT provides a unique environment for examining how HIV affects cell movement, as well as reconciling two seemingly disparate results: 1) HIV or expression of viral proteins augments cell motility, potentially leading to virus dissemination; and 2) viral proteins and cellular factors acting as chemoattractants may lead to recruitment of other cells to the site of infection and inhibit cell egress, promoting the maintenance of a viral reservoir in the gut. As data from our laboratories would support this dual scenario, we hypothesize that during the acute phase of HIV infection, viral proteins augment the motility of infected gut mucosal lymphoid cells from sites of infection to the periphery. During the chronic stage of HIV infection, viral and cellular chemoattractant factors in the tissue may play a more dominant role, facilitating recruitment of uninfected cells into the gut mucosa. The work outlined in this proposal will directly address this hypothesis by examining the impact of HIV infection on the migration of target cells in the GALT.
The Specific Aims are to: 1. Define the acute effects of HIV infection on the motility of GALT immune cells, utilizing: a) isolated gut mucosal mononuclear cells; and b) whole-tissue GALT explant organ cultures from HIV-seronegative individuals. 2. Characterize the viral and cellular chemotactic signals that promote target cell migration, infection, and maintenance of a GALT viral reservoir during chronic HIV infection, using explants from HIV-infected volunteers. The proposed studies explore unique mechanisms by which HIV may disseminate from initial sites of infection, using the novel model system of cultured explants of gut mucosa. Our results may lead to previously unexplored preventive and therapeutic strategies for HIV infection and AIDS. ? ?
