Recent developments in HIV pathogenesis have documented the widespread dissemination of HIV into multiple lymphoid organs including the thymus. The low CD4 T cell counts in AIDS patients may reflect in part damage to the thymus and the inability to generate new CD4 T cells from bone marrow stem cells. New data has shown that CD4 T cell counts can increase transiently (although not to normal levels) in HIV-infected patients if the viral burden is decreased by antiretroviral therapy. Efforts to reconstitute the immune system in HIV infection must address the question of whether post-natal T cell maturation requires a functioning thymus or whether expansion of self-renewing T cells in the periphery is sufficient. A related question is whether a functioning thymus is needed for T cell development in the context of a therapy which destroys peripheral T cells (such chemotherapy prior to bone marrow stem cells transplantation). We propose a 2-year pilot study (Study B) in 24 HIV-infected subjects who have CD4 T cell counts between 200 and 400/mm3. The patients will all be treated intensively with combination antiretroviral therapy to decrease viral burden. Eight of the patients will receive no other therapy, eight will receive a post-natal cultured thymus transplant, and eight will receive cytotoxic lymphocyte (CTL) therapy. The primary hypothesis being tested in Project III is whether thymic transplantation will increase CD4 T cell counts and other measures of T cell function compared to the antiretroviral therapy group which does not receive thymic transplants. Flow cytometry and T cell responses to specific antigens will be studied to determine whether the regenerating T cells in the patients are derived from peripheral T cells or from development of T cells in the thymus. In combination with Project II and the Molecular Virology Core, we will determine whether thymic transplantation affects viral burden and CTL precursor frequency. In the last two years of the grant, an additional clinical trial will be designed depending on the results of the first two years for all three projects. If project III shows that thymus transplants are viable and contain host thymocytes, then thymic transplantation will be combined with the bone marrow transplants in lymphoma, and possibly non-lymphoma, patients depending on the results of Project I. If the cytotoxic lymphocyte (CTL) therapy of Project II results in a decrease in viral burden, then a new group of patients will be treated with antiretroviral agents, thymus transplant and CTLs. Thymic transplantation may become an important component of the immunologic reconstitution of HIV infection.
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