The Human T-cell Leukemia/Lymphoma Virus (HTLV-1) is an endemic, and now epidemic, virus known to cause a virulent and aggressive lymphoma/leukemia in a subset of infected patients after a long latent period. In addition, HTLV-1 is associated with a new disease known as HTLV-1-associated arthropathy (HAAP). This inflammatory arthritis is characterized by the presence of the HTLV-1 provirus in DNA from peripheral blood lymphocytes and synovial cells. Mice transgenic for the HTLV-1 genome manifest an inflammatory arthropathy that resembles rheumatoid arthritis. Regulation of cellular genes by human retroviruses is likely to be a crucial link in their pathogenic activities, and may be responsible for such diverse sequellae as leukemogenesis, arthropathy, Sjogren's syndrome, SLE, or polymyositis. We have found a new way in which HTLV-1 aberrantly regulates inflammatory and collagenase gene expression in infected cells. HTLV-1 encodes a novel a trans-activating activity encoded in the viral Long Terminal Repeat (LTR). The cellular genes regulated by the viral LTR include class I MHC antigens, lymphocyte activation antigens, inflammatory and chemotactic cytokines, early growth-related genes, and collagenase IV. Any and all of these gene products might contribute to the development of a destructive, inflammatory arthropathy. The ultimate objectives of this project are to elucidate, at a molecular level, the mechanisms by which the HTLV-1 LTR trans-activate cellular genes in infected cells, and the consequences of this trans-activation. 1) The retroviral LTR sequences responsible for trans-activation of Class I MHC, inflammatory cytokine, protease, and T cell activation antigen genes will be identified. The molecular mechanism of trans-activation will be established, and the biological consequences of retroviral trans- activation of these genes will be determined. The cisacting promoter regions of HTLV-1-responsive inflammatory genes will be mapped and defined, and other cellular genes activated by the HTLV-1-LTR will be determined. 2) The effects of this LTR activity on inflammatory/cytokine/protease gene expression in human synovial cells will be examined. 3) The biological consequences of this aberrant control of cellular genes by HTLV-1, and how this dysregulation contributes to the arthropathy caused by the virus, will be studied. Our short-term goal is to determine how this activity of the virus regulates these genes and if this new viral activity may mediate the inflammatory arthropathy caused by the virus. Our long-term goal is to develop ways of circumventing this abnormal regulation of gene expression by HTLV-1, to prevention the arthropathy. This pilot project will allow us to set up biological modes to determine the role and contribution of this new gene product in HTLV-1-induced inflammatory disorders.
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