Activation of HTLV1 Gene Expression and Oncogenesis

DESCRIPTION: (provided by applicant) Infection with the human T-cell leukemia virus type 1 (HTLV-1) can have diverse clinical effects. ranging from asymptomatic infection to the development of the fatal malignancy, adult T-cell leukemia/lymphoma (ATL) HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP), or a variety of autoimmune dnd inflammatory diseases. The differential pathogenesis of these disorders undoubtedly involves complex interactions between HTLV-1 and the infected host. These interactions are likely to be both at the level of the whole organism (i.e. immune response to the virus) and at the level of the individual infected cell, in which cellular regulatory mechanisms could influence viral gene expression. Recent studies from our laboratory have demonstrated that HTLV1 infection of human T cell lines can be essentially latent, with only very low levels of HTLV-1 gene expression. HTLV-1 gene expression can be activated from latently infected cell lines by treatment with immune activation related stimuli, such as phytohemagglutinin (PHA) and phorbol esters (PMA). We have further shown a marked, synergistic activation of HTLV- 1 gene expression induced by T-cell activation stimuli in conjunction with the HTLV-1 Tax transcriptional transactivator. These data suggest interesting models for regulation of HTLV-1 gene expression by cellular activation stimuli and an overall hypothesis that immune activation stimuli may enhance HTLV-1 gene expression. thus contributing to the development of diseases such as ATL. Immune stimulation of infected I cells would enhance expression of HTLV-1 gene products, such as the oncogenic Tax protein Tax expression in turn would induce T cell proliferation, leading to the poly-. and oligoclonal T cell proliferation associated with HTLV-1 induced neurologic and autoimmune disease, and ultimately to the monoclonal proliferation of AlL. In this project, we will examine the mechanisms responsible for the induction of HTLV-1 gene expression by immune activation stimuli and the possible biological implications of this activation, as they may contribute to disease pathogenesis. The specific aims of the project are to: (1) Characterize the molecular mechanisms by which immune activation stimuli induce HTLV-1 gene expression, focusing on the roles of the HTLV-1 LTR and HTLV-1 Tax in the synergistic activation induced by immune activation stimuli; (2) Study the effects of viral LTR sequences and immune activation stimuli on HTLV 1 replication and T-cell transformation; (3) Determine if HTLV-1 lax will cooperate with immune 'activation stimuli in the regulation of cellular target genes that may contribute to HTLV-1 pathogenesis and oncogenesis: and (4) Determine if immune activation stimuli will induce T cell lymphomas in HTLV-1 LTR-Tax transgenic mice. thus providing a possible model of events involved in the pathogenesis of human AlL.