The Human T-cell leukemia Virus type 1 (HTLV-l) is a representative member of a family of human retroviruses. Serologic and epidemiologic evidence has implicated this Virus as the causative agent of a group of lymphoproliferative diseases collectively known as Adult T-Cell Leukemia/Lymphoma (ATLL). HTLV-L transforms primary CD4 positive lymphocytes in vitro. However, because the viral genome lacks any sequence homology to any recognized oncogene, and the site of proviral integration varies from one tumor to another, the mechanism by which HTLV-L transforms cells appears to be different than for other retroviruses. Recent evidence obtained using a novel Herpesvirus (H.
s aimi ri)-based vector has proven that the 3' end of the HTLV-L genome, the X-region, is necessary for the lymphocyte immortalization process. The goal of this proposal will be to define which of the coding sequences within the X-region, and what functional properties of their encoded proteins, are necessary for the immortalization and phenotype of the transformed lymphocytes. We intend to use the H.
s aimi ri vector to introduce mutant constructions of the X-region into primary lymphocytes so that we will be able to identify which individual coding sequence(s) within the region is necessary for immortalization and/or transformation. We will also perform extensive mutagenesis of the x-region gene product tax, the major transactivating protein of HTLV-I. This protein has been shown to possess oncogenic potential in transgenic Mice and various fibroblast systems. Through this mutagenesis we hope to define functional domains within the tax protein, and determine the relationship between transactivation and transformation. Finally, utilizing a recently developed and highly efficient vector system based on the Human Immunodeficiency Virus (HIV), we will determine whether the x-region alone is sufficient for human lymphocyte immortalization or whether components of the H.
S aimi ri vector are contributing to the
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