Depletion of CD4+ T lymphocytes is one of the fundamental characteristics of the immunodeficiency induced by HIV infection. Existing therapies for HIV-infected people have little long-term impact on reversing this central feature of AIDS, and even treatments that result in modest increases in CD4+ T lymphocytes do not appear to restore production of naive T lymphocytes. Infection of the thymus by HIV significantly impairs de novo production of new T cells, and this deficit is likely to thwart efforts to reconstitute immunity by antiviral therapy or stem cell gene therapy. Restoration of immune function in HIV-infected people is therefore likely to require restoration of thymic function. Recent evidence from Dr. Megan Sykes' laboratory has demonstrated the capacity of porcine fetal thymus transplants to reconstitute normal murine T cell populations in thymectomized, T cell-depleted immunocompetent mice. However, if these findings are to provide a new approach to the treatment of HIV infection, it will be essential to determine whether or not porcine thymic grafts can also perform this function in SIV-infected primates. Thus, the overall goal of this proposal is to use the SIV/macaque model to determine the conditions required to achieve engraftment of, and host T cell reconstitution by, pig thymus and hematopoietic stem cells in SIV-infected hosts. Specifically, we will: 1. Use as in vitro model to evaluate the ability of pig thymic tissue to support T cell differentiation of primate CD34+ hematopoietic progenitor cells, 2. Examine the ability of pig thymus transplants to reconstitute T cells in SIV=infected rhesus monkeys receiving antiretroviral therapy and determine the requirement for host conditioning at different stages of disease, and 3. Employ porcine hematopoietic stem cells in combination with swine thymic grafts to reconstitute immune function in SIV-infected macaques. If successful, these studies should establish the framework for the use of xenogeneic thymic and hematopoietic cells to restore T cell immunity in HIV-infected people.
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