Human T-lymphotropic virus type 1 is associated with diseases of proliferation and degeneration in humans. Previous studies utilizing a transgenic mouse model expressing the HTLV-1 tax gene, suggested that this gene product alone may be capable of inducing both categories of disease in mice. In humans, the virus induces lymphoproliferative, neurodegenerative and musculodegenerative diseases. In mice, disease occurs at the site of protein expression which is determined in the first model by the viral LTR. In this proposal, the original LTR-tax model addition, high levels of tax protein expression will be retargeted to the organs affected in humans. Expression of the tax protein will be directed to lymphoid and brain tissue by use of a Thyl.2 expression vector, to neurons specifically by use of the rat neuron specific enolase promoter and specifically to astrocytes by the murine glial fibrillary acidic protein promoter. The biologic effects of an additional HTLV-1 regulatory protein, rex will also be assessed by introduction into transgenic mice. This protein may be important in control of viral latency and tropism in humans. Experiments will test: 1) The capability of tax to induce proliferation in mature or immature lymphocytes. 2) The importance of secondary events in the induction of leukemia. 3) Whether tax can induce neurodegenerative disease. 4) Whether rex can alter site of expression and biologic effects of tax. 5) Qualitative and quantitative aspects of tax mediated transcriptional trans- activation in vivo.
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