CD4 lymphocyte depletion associated with HIV infection is a dynamic process, reflecting both the destruction of peripheral T lymphocytes as well as a reduced output of lymphocyte production. Production of new CD4 cells in the thymus to replace those destroyed or damaged by retroviral infection is likely to play a pivotal role in the maintenance of immune competence. Thymic abnormalities have been reported in both SIV and HIV infection; however experimental limitations have precluded detailed laboratory studies of the effects of retroviral infection on T cell development. Previous experimental in vitro and in vivo studies have shown that immature thymocytes are a target for HIV-1 and SIV infection, and have suggested that viral replication may contribute directly to thymocyte death. Their hypothesis is that thymic infection may result in interruption or disruption of T cell development, and that this may contribute to the accelerated nature of the disease in both children and adults. The investigators have recently developed a novel, highly efficient system of in vitro T cell differentiation that facilitates the differentiation of both rhesus monkey and human progenitor cells into thymocytes and mature T cells. The overall aims of this proposal are to elucidate the various targets of retroviral infection in the thymus, and by performing detailed studies on cell function, to better understand the role of retroviral infection within the thymus on alterations in T cell ontogeny and thymocyte death.
Specific aims i nclude: (1) To determine the thymotropism and kinetics of SIV replication in thymic stromal cultures. (2) To examine the effects of SIV infection on T cell development in vitro. (3) To examine the mechanisms associated with thymocyte death during SIV infection.
