The goal of Project 1 is to develop effective methods for reducing HIV viral burden and enhancing immune reconstitution in individuals with HIV infection via treatment with myeloblative therapy and transplantation of hematopoietic stem cells. Sequential clinical trials will be performed in this project. In the first pilot trial, because of the anticipated morbidity of this treatment approach, patients with AIDS related lymphoma will be treated. The first clinical trial will determine: l) whether myeloblative therapy combined with antiretroviral therapy will durably reduce HIV burden, 2) the rate, severity, and major cause of morbidity in patients with HIV infection undergoing treatment with combinations of anti-retroviral agents and myeloablative therapy, 3) whether T-cell depleted allogeneic peripheral blood stem cells can be successfully transplanted in patients with HIV infection, 4) immune reconstitution following stem cell transplantation, and 5) the effects of this therapeutic strategy on AIDS related lymphoma. Following completion of the first clinical trial, a second set of stem cell transplantation clinical trials will be designed to address the major obstacles to stem cell transplantation, control of HIV infection, and immune reconstitution that were identified in the first clinical trial. Additional therapies which are under development within this SPIRATS application and elsewhere at Duke will be incorporated to address these issues. These therapies include thymus transplantation, administration of HIV specific CTLs, and genetic modification of the transplanted stem cells.

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Markert, M L; Alvarez-McLeod, A P; Sempowski, G D et al. (2001) Thymopoiesis in HIV-infected adults after highly active antiretroviral therapy. AIDS Res Hum Retroviruses 17:1635-43
Markert, M L; Hicks, C B; Bartlett, J A et al. (2000) Effect of highly active antiretroviral therapy and thymic transplantation on immunoreconstitution in HIV infection. AIDS Res Hum Retroviruses 16:403-13
Markert, M L; Kostyu, D D; Ward, F E et al. (1997) Successful formation of a chimeric human thymus allograft following transplantation of cultured postnatal human thymus. J Immunol 158:998-1005
Davis, C M; McLaughlin, T M; Watson, T J et al. (1997) Normalization of the peripheral blood T cell receptor V beta repertoire after cultured postnatal human thymic transplantation in DiGeorge syndrome. J Clin Immunol 17:167-75