CD4 lymphocyte depletion is one of the fundamental characteristics of the immunodeficiency induced by HIV infection. Existing therapies for HIV-infected individuals have advanced so that viral replication can be controlled more effectively. However, despite these significant therapeutic developments, generally only modest increases in CD4+ T cells occur. Furthermore, thymic destruction as a consequence of HIV results in impaired de novo production of new T cells so that the emergence of naive T cells evaluated by flow cytometry is generally incomplete. The rate of decline of recent thymic emigrants has been correlated with the overall decrease in CD4 counts in HIV- 1 infected individuals. HIV infection results in thymic atrophy and thymocyte depletion that in adults appears to be somewhat irreversible. Full restoration of immune function in some HIV-infected people is therefore likely to necessitate restoration of thymic function. Recovery of thymic function, even in the context of HAART, is likely to require novel forms of therapy, including thymic transplantation in a subset of patients. Recent evidence from this group has demonstrated that porcine thymus can support human and non-human primate Iymphopoiesis. In addition, we have had limited but encouraging results to suggest that engraftment of porcine thymic tissue in SIV-infected macaques is feasible. However, even animals with advanced SIV infection have the capacity to reject porcine thymus, necessitating use of host conditioning to achieve porcine thymic engraftment and function. Based on these observations, the overall goal of this proposal is the optimization and further evaluation of immune reconstitution achieved by xenotransplantation of porcine thymus in SHIV-infected macaques. Specifically, we will: 1) Determine the optimal conditioning requirements to achieve porcine thymic engraftment in SHIV infected macaques 2) Evaluate the general immune reconstitution achieved with porcine thymic transplantation; 3) Evaluate SHIV-specific immune responses after porcine thymic transplantation. If successful, these studies should establish the basic framework for the use of xenogeneic thymic tissue to assist in the restoration of T cell function in HIV-infected individuals.
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