Since loss of CD4 positive cells is the hallmark of disease progression in HIV infection, understanding the interaction between HIV and the developing T cells in the thymus is crucial for gaining better insight into disease progression. The thymus is essential for normal T cell development and consists of predominantly CD4 positive immature T cell which as we and others have shown can be readily infected with HIV in vitro and in vivo. A productive HIV infection depends on virus strain and on the activation state of the target cell. Our hypotheses are; 1) that thymocyte subsets which are activated and/or proliferating are principle targets for HIV infection; 2) that cytopathic viral strains affect thymocytes at an earlier stage of maturation than non-cytopathic strains and 3) that depletion of thymocytes which produce IFN-gamma results in increased HIV expression by thymocytes and contributes to immunodeficiency. We have an unique opportunity to test these hypotheses using clinical viral isolates in a three-dimensional model comprised of in vitro thymocyte suspension culture, thymus organ culture and thymus grafts in the SCID/hu mouse. The following is an outline of our experimental strategy. We will test which thymocyte subsets are infected and expressing virus y sorting of immature and mature thymocytes subsets after in vitro and in vivo (SCID/hu mouse) infection of thymocytes with isolates of different pathogenicity. In addition, we will compare the functions of HIV-infected with sham-infected thymocyte subsets. We will investigate the regulation of HIV infection in the thymus by IFN-gamma, since we have found that IFN-gamma inhibits HIV production by thymocytes in vitro. Low iFN-gamma levels at birth could be one factor in perinatal HIV transmission. The study of the effects of viral isolates with different cytopathogenicity on the maturation and function of immature T lymphocytes in the thymus provides an opportunity to define indicators of disease aggressiveness in pediatric patients and specific targets for medical intervention.
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