Human T-Cell leukemia virus type 1 (HTLV1) is the cause of adult T cell leukemia/lymphoma ATLL and HTLV1 -associated myelOpathy (HAM). Lymphocytes immortalized in vitro by HTLV1 have morphologic, antigenic, and biochemical features that closely resemble the malignant cells identified in ATLL. HTLV1 immortalization of lymphocytes appears to be the consequence of several steps that depend on specific viral and cellular factors. The first step, and the focus of the current investigation, is the mitogenic activation of normal lymphocytes by HTLV1 infected cells. First, we will use transgenic mice expressing one or two viral proteins, TAX and/or ENV to examine lymphocyte proliferation and activation in an in vivo model system. We will examine whether lymphoproliferative disorders occur spontaneously in such transgenic mice, or can be induced by an antigenic stimulus. We will also examine the role of p53, bcl2, and cytokines in leukemogenic activity. In addition, we will construct transgenic mice with mutations in the NF-kB or CREB/ATF activation domains of TAX to assess their roles in lymphoproliferation. Second, we will use a functional proviral clone of HTLV1, capable of producing viral particles, to examine the viral factors critical for mitogenic activation. We will examine mutations in TAX that either inactivate the NF-kB or CREB/ATF activation domains or affects its ability to cooperate with RAS. Mutations in ENV will examine the role of the cytoplasmic tail and membrane-spanning domains in T cell proliferation. In addition, several site-directed mutants near fusion domains in the surface envelope protein will be studied. Mutations in ENV, ROF, and TOF will also be examined. These studies provide an important animal model system, and an important infectious proviral clone for future studies. Furthermore, the described experiments should provide novel insights into the mechanisms of leukemogenesis utilized by HTLV1.
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