FUNCTIONAL ANALYSIS OF THE HUMAN T-LYMPHOTROPIC VIRUSES

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The long term goals of this proposal are to define the role of HTLV-1 like viruses in inducing human disease, including malignant lymphoid neoplasia and degenerative neurological disorders, and to derive transgenic mice carrying genes from these HTLV-like viruses to delineate the mechanisms of disease pathogenesis. This application is composed of four specific but interrelated aims: [1] to define using transgenic mice and at the single cell level the tissue-specificity of the prototype HTLV-1 long terminal repeat (LTR), either in the absence or presence of the HTLV-1 trans-activator (tax); [2] to determine using transgenic mice the differences between HTLV-2 and the prototype HTLV-1, both in terms of LTR specificity and role of the tax gene in inducing pathogenesis; [3) to clone using PCR amplification HTLV-like sequences directly from the involved tissues of patients with Tropical Spastic Paraparesis (TSP), and to compare their DNA sequences with the prototype HTLV-1; and [4) to ascertain using transgenic mice the functional significance of the base substitutions detected among the various HTLV-like sequences from TSP patients, and to determine whether such substitutions are responsible for altering disease phenotypes.