Despite advances in anti-retroviral chemotherapy and limited attempts at hematopoietic cell transplantation in conjunction with such therapy, effective approaches to achieving immune reconstitution in patients with advanced AIDS have not yet been developed. A major limitation to these approaches may be the absence of a functioning host thymus, which is the central organ for T cell development and is a major target of destruction by HIV. Provision of a replacement thymus in conjunction with the above therapies is likely to allow more efficient recovery of T cell immunity. Our recent studies in a murine model have demonstrated that a xenogeneic porcine fetal thymus graft can replace the host thymus to allow the development of mature and functional host (murine) CD4+ T cells. Swine provide a readily available source of fetal thymic tissue, which, like swine T cells, is resistant to HIV infection. Swine can be rapidly bred under quality-controlled conditions that would allow their use as donors to immunocompromised humans. The goal of the studies in this project is to determine the capacity of fetal (or neonatal) swine thymic grafts given with or without swine hematopoietic stem cells in combination with optimized combination anti-retroviral chemotherapy, to reconstitute functional T cells in the presence of immunodeficiency infection. The optimal way of applying this approach will be determined by in vitro studies and murine and primate models in this program. Murine studies (Project 1) will determine the effect of HIV on murine and human thymopoiesis in pig thymi, and the degree of immunocompetence obtainable for T cells differentiating in a xenogeneic thymus. Project 2 will apply these results to the development of a swine to primate thymic transplantation model. In Project 3, this approach will be extended to SIV infected primates in order to determine the host conditioning requirements and the potential of thymic replacement alone to reconstitute immune function at various stages of disease. If these studies suggest that xenogeneic hematopoietic stem cell engraftment and reconstitution will be required in addition to thymic replacement in order to achieve immunocompetence in the setting of advanced retroviral infection, then we will make use of results of studies in Project 1 evaluating the need for swine antigen-presenting cells (APC) to allow adequate immune function of swine T cells and the ability of swine-specific cytokines to induce differentiation of swine hematopoietic cells. Application of these results to Project 2 will lead to the development of a regimen allowing both swine hematopoietic cell and thymic engraftment in SIV-infected monkeys in Project 3. The studies in this Program may lead to the development of a novel clinical strategy for the treatment of AIDS.