This proposal is based upon the assertion that the formation of T lymphocyte and dendritic cell derived syncytia in lymphoid tissue plays a crucial role in the depletion of the these respective cell types during HIV infection and in the subsequent manifestations of AIDS. The hypothesis is that the motile behavior of syncytia in vivo may be involved in white blood cell death, in the dissemination of the virus, and in the degeneration of lymphoid tissue in HIV-infected patients with falling CD4+ T cell numbers. In the proposed research, experiments are planned to test whether syncytia formed in the axillary lymph node and adenoid or tonsillar tissue of HIV-infected patients (with falling T cells counts) exhibit the same pathological behaviors demonstrated for syncytia formed in vitro. First, a detailed characterization of the behavioral capabilities of T cell derived syncytia formed in vitro will be completed. This will include a behavioral description of the steps in T cell-derived syncytium fusion and syncytium-mediated T cell chemotaxis, an analysis of the role of actin in these behaviors and, a characterization of the T cell chemoattractant released by syncytia. Second, the motile behavior will be determined for Langerhans' cells isolated from mucosal epithelium and syncytia generated through HIV infection of Langerhans' cells and T cells. This characterization will include; a computer-assisted analysis of translocation and dynamic morphology, motility cycle, organization of F-actin and microtubules, nuclear morphology, and chemoattractant release. Third, syncytia will be isolated from the axillary lymph node and adenoid or tonsillar tissue of HIV-infected volunteers with falling T cell counts. These will be tested for the behavioral characteristics demonstrated for syncytia in vitro. The mechanisms in vivo for T cell and Langerhans' cell depletion are not understood. It is the belief of the PI that HIV-induced syncytium formation may play a role in the depletion of both cell populations and that a need exists to critically analyze the behavioral phenotype of such syncytia in order to assess their potential role in disease progression. Furthermore, syncytium formation may serve as an indication of HIV progression.
