Studies have suggested that differentiated dendritic cells and activated macrophages in peripheral blood (PB) and lymph nodes (LN) contain human T cell lymphotropic virus type I (HTLV-I) proviral DNA that may serve as a template for highly regulated low level expression of virus-specific RNA and proteins including the viral transactivator, Tax. The Principal Investigator (Principal Investigator) proposes that this expression pattern is the result of a highly specific differentiation process that alters the levels, and possibly the activity of several cellular transcription factors that activate and maintain a low level of LTR activity and is of central importance in the induction of a neuroinflammatory process that involves the neurotoxic action of HTLV-I-specific cytotoxic T cells and dysregulation of CNS cytokine pathways that leads to the neurologic disorder, tropical spastic paraparesis (TSP). The Principal Investigator will examine cellular and viral factors that regulate HTLV-I activation with new emphasis placed on regulation of viral expression during differentiation of hematopoietic cells such as CD34+ progenitor cells and cells of the monocytic lineage including dendritic cells, macrophages, and brain microglial cells. The studies will focus on the cellular AP-1 and Sp transcription factor families and their role in modulating basal and Tax-mediated transactivation during hematopoietic cell differentiation.
The aims of this competing renewal will examine (1) cellular regulation of HTLV-I LTR activation by Sp and AP-1 families during differentiation of the monocytic lineage in bone marrow (BM), PB, and brain; (2) intracellular localization of HTLV-I Tax and its impact on LTR Tax responsive element 1 (TRE-1) and TRE-2 function, Sp and AP-1 expression, and the function of selected Sp- and Ap-1 binding site-containing monocytic promoters during differentiation in monocytic cell lines; (3) Tax-mediated LTR activation in primary cells of the monocytic lineage in BM, PB, and brain utilizing lentiviral vectors and HTLV-I molecular clones; and (4) molecular interaction of Tax with Sp and AP-1 factors with TRE-1 and cis-acting elements in selected monocytic promoters. These studies could lead to new therapeutic approaches to prevent and/or treat TSP or other neuroinflammatory diseases.
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