EXCEED THE SPACE PROVIDED. Since the thymus plays an essential role in the development of the immune system, it is important to understand the effects of HIV-1 infection on T cell function in the thymus. Increasing evidence for its functional relevance into late adulthood underscores the likely importance of the thymus in immune dysfunction and immune reconstitution in HIV-1 immunopathogenesis. Although peripheral T cell dysfunction and abnormal maturation has been a subject of intense investigation in HIV-1 infection, the contribution of thymus dysfunction as a factor remains poorly understood. Our previous work has demonstrated the interplay of different cell populations through cytokine networks in thymocyte development. In our experimental models of thymus infection, we have observed changes in thymocyte function after HIV-1 exposure, including production of the key cytokine IFN-,/. Furthermore, although we have shown that coreceptor tropism is an important determinant of pathogenicity in the thymus, some primary viral isolates from infants differed in their pathogenicity independently of tropism, strongly suggesting that other virologic factors are crucial. Therefore, immunologic and viral factors that affect HIV-1 pathogenesis in the thymus need to be elucidated.
Our specific aims concerning HIV-1 infection of the thymus are to: To determine the effects of HIV-1 on cytokine production and cytotoxic functions of thymocytes To delineate thymocyte subset composition and T cell repertoire resulting from HIV-1 infection with isolates of different pathogenicity. To define the contribution of nef to HIV-1 pathogenesis in the thymus. We have an unique opportunity to test these aims using primary clinical viral isolates with well-defined behavior in thymus infection in three models: in vitro thymocyte suspension culture, thymus organ culture, and thymus grafts in the SCID-hu mouse.
Our aims are designed to investigate whether infection leads to production of functionally/maturationally abnormal T cells or an altered T cell repertoire, and to what extent Nef (which has a central role in the pathogenesis of HIV-1 and SIV) may contribute to these phenomena. These studies will provide an opportunity to explore an important component in the pathogenesis of HIV-l-induced immune damage to which pediatric patients may be particularly susceptible, with ramifications in immune reconstitution. PERFORMANCE SITE ========================================Section End===========================================
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