Human T cell leukemia virus type 1 (HTLV-1) has been identified as the etiologic agent of adult T cell leukemia (ATL) and the neurologic disorder, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Extensive studies performed in HAM/TSP patients have demonstrated that neurologic disease associated with HTLV-1 infection is due to a hyperinflammatory disease state induced by the generation of an intense cytotoxic T cell (CTL) response with large numbers of CD8+ CTLs directed against the Taxi 1 -19 peptide indicating that Tax is available for immune recognition by antigen presenting cells (APCs) that likely contributes to the overly robust Tax-specific CTL response observed in HAM/TSP. The HYPOTHESIS guiding the proposed investigations in this competitive renewal application is that biologic and immunologic activities of the HTLV-1 transactivator protein Tax within the nuclear, cytoplasmic, and extracellular compartments lead to functional alterations in secondary target cell populations (including bone marrow progenitor cells, cells of the monocyte-macrophage lineage, APCs such as dendritic cells, macrophages and B cells and astrocytes). Ultimately, this leads to a hyperactive Tax-specific CTL compartment along with perturbation of additional components of the immune system that results in the neurologic deficits observed in HAM/TSP.
The specific aims that will address specific aspects of this general hypothesis are to (1) determine the effects of AP-1, C/EBP, and Sp transcription factor families on Tax-mediated HTLV-1 LTR regulation in selected secondary target cell populations within the context of an integrated LTR and HTLV-1 infectious molecular clone; (2) define DNA-protein interactions involved in basal and Tax-mediated HTLV-1 LTR regulation by AP-1, C/EBP, and Sp factors within the context of chromatin and utilizing real-time kinetic analyses; (3) define the protein-protein interactions in secondary target cell populations that guide nuclear export, cytoplasmic transport, and secretion of HTLV-1 Tax; and (4) examine the impact of extracellular Tax on the biologic, physiologic, and immunologic function of APCs with respect to the induction of a Tax-specific CTL response. The proposed investigations will provide novel information concerning the molecular pathogenesis of HAM/TSP and facilitate the biomedical translational development of therapeutic initiatives to prevent and/or treat HTLV-1-induced neuroinflammatory disease. ? ? ?
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