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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA050234-01A1
Application #
3194614
Study Section
Experimental Virology Study Section (EVR)
Project Start
1990-04-01
Project End
1994-02-28
Budget Start
1990-04-01
Budget End
1991-02-28
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Xu, X; Kang, S H; Heidenreich, O et al. (1996) Rapid PCR method for site-directed mutagenesis on double-stranded plasmid DNA. Biotechniques 20:44-7
Xu, X; Dai, Y; Heidenreich, O et al. (1996) Adenovirus-mediated interferon-gamma transfer inhibits growth of transplanted HTLV-1 Tax tumors in mice. Hum Gene Ther 7:471-7
Xu, X; Kang, S H; Heidenreich, O et al. (1996) Sequence requirements of ATF2 and CREB binding to the human T-cell leukemia virus type 1 LTR R region. Virology 218:362-71
Heidenreich, O; Xu, X; Nerenberg, M (1996) A hammerhead ribozyme cleaves its target RNA during RNA preparation. Antisense Nucleic Acid Drug Dev 6:141-4
Xu, X; Heidenreich, O; Nerenberg, M (1996) HAM/TSP and ATL: persistent paradoxes and new hypotheses. J Neurovirol 2:60-9
Heidenreich, O; Xu, X; Swiderski, P et al. (1996) Correlation of activity with stability of chemically modified ribozymes in nuclei suspension. Antisense Nucleic Acid Drug Dev 6:111-8
Brown, D A; Xu, X; Nerenberg, M (1996) Genomic footprinting of HTLV type I and HIV type 1 in human T cell lines. AIDS Res Hum Retroviruses 12:829-32
Xu, X; Heidenreich, O; Nerenberg, M (1996) Role of kinases in HTLV-I transformation. J Investig Med 44:113-23
Heidenreich, O; Kang, S H; Brown, D A et al. (1995) Ribozyme-mediated RNA degradation in nuclei suspension. Nucleic Acids Res 23:2223-8
Xu, X; Brown, D A; Kitajima, I et al. (1994) Transcriptional suppression of the human T-cell leukemia virus type I long terminal repeat occurs by an unconventional interaction of a CREB factor with the R region. Mol Cell Biol 14:5371-83

Showing the most recent 10 out of 16 publications