Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
HUMAN T-CELL LEUKEMIA VIRUS TYPE I (HTLV-I): STUDIES OF DISEASE MECHANISMS IN A TRANSGENIC MOUSE SYSTEM
The Human Retroviruses. Gallo RC and Jay G, eds. San Diego, Academic Press, p. 227-43, 1991.. Unique Identifier : AIDSLINE ICDB/92678730 Hinrichs SH; Chen L; Fontes J; Jay G; Dept. of Medical Pathology, Sch. of Medicine, Univ. of; California, Davis, CA 95616
Abstract:
HTLV-I has been associated with a wide range of human disease including adult T-cell leukemia (ATL), tropical spastic paraparesis, polymyositis, and possibly multiple sclerosis. Results obtained using a transgenic mouse experimental system are reviewed, including current problems and molecular considerations; value of a transgenic approach to the study of HTLV disease; effects of the HTLV tax gene in transgenic mice; and effects on the thymus, salivary gland, and nerve sheath. It is clear that the HTLV-I long terminal repeat (LTR), in the presence of its transcriptional trans-activator (the Tax protein), is active in only a small subset of cell types in the transgenic mice. These include cells in the salivary gland, nerve sheaths, and muscle. It is not clear, however, whether the lack of expression in most other cell types is due to the methylation of cis-acting elements with the LTR, the presence of LTR-responsive negative regulatory factors, or the absence of LTR-responsive positive trans-acting factors. The most striking observation in this transgenic mouse model is that expression of a single gene from HTLV-I, the tax gene, suffices to induce tumor at different target sites. Benign tumors developed from ductal cells in the salivary gland and neurofibroblasts in the nerve sheath. It appears that only select cell types have subcellular targets for the HTLV-I Tax protein. The fact that numerous lesions arise simultaneously at widely separated body sites in each animal at a very early age indicates that the Tax protein can act 'directly' to induce cell proliferation and hyperplastic growth in involved tissues. The occasional finding of a malignant tumor, and then only in older mice, suggests the involvement of a second genetic event in the progression of disease. This implies that the development of ATL in patients is not the sole action of HTLV-I. The gene for granulocyte-macrophage colony-stimulating factor (GM-CSF) is one that is trans-activated. Not only are infected cells affected by HTLV-I, but uninfected cells in the same individuals can be affected profoundly by the activation and secretion of growth-modulating factors. However, GM-CSF is not always associated with tax-induced proliferation. (42 Refs)
Keywords: Animal Cell Transformation, Neoplastic/GENETICS/PATHOLOGY Gene Expression Regulation, Viral/PHYSIOLOGY Genes, pX/GENETICS/PHYSIOLOGY HTLV-I/*GENETICS/PATHOGENICITY Leukemia-Lymphoma, T-Cell, Acute, HTLV-I-Associated/*GENETICS/ MICROBIOLOGY/PATHOLOGY Lymph Nodes/PATHOLOGY Mice Mice, Transgenic/GENETICS Myelin Sheath/PATHOLOGY Repetitive Sequences, Nucleic Acid/GENETICS/PHYSIOLOGY Salivary Glands/PATHOLOGY Thymus Gland/PATHOLOGY Virus Replication/GENETICS/PHYSIOLOGY MONOGRAPH REVIEW
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Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
