The human T-cell leukemia/lymphoma virus type 1 (HTLV-I) is a complex retrovirus. HTLV-I infection is epidemiologically associated with an aggressive and fatal T-cell type leukemia/lymphoma designated as Adult T-cell Leukemia/ Lymphoma (ATLL). HTLV-I infection is also associated with a progressive myelopathy designated Tropical Spastic Paraparesis/ HTLV-I-Associated Myelopathy (TSP/HAM) of probable immune-mediated pathogenesis. The virus is transmitted through sexual contacts, contaminated blood and from mother-to-child by breast feeding and it is estimated that 20 to 30 million people worldwide are infected with HTLV-I. The provirus genome encodes a viral transactivator, Tax, which is critical for viral replication, cellular transformation and pathogenesis. Tax stimulates transcription through CREB, NF-kappaB and SRF resulting in deregulated expression of various cellular genes. While NF-kB activation appeared important for short term IL-2-dependent proliferation, unexpectedly neither the activation of CREB/ATF nor NF-kB were sufficient to support long term T-cell immortalization by Tax and a novel domain was identified. The goals of this proposal are to understand the sequence of events that take place during Tax-mediated human T-cell immortalization (IL-2-dependent) and transformation (IL-2-independent). Based upon our data three aims are proposed:
Aim l. Characterize cellular pathways involved in short term and long term Tax-mediated IL-2 dependent T-cell proliferation and immortalization and identify the cellular genes involved to bypass each crisis.
Aim 2. Study of Tax's effect on hTERT promoter stimulation and telomerase activity.
Aim 3. Identify cellular or viral genes involved together with Tax in the switch from IL-2-dependent to IL-2-independent T-cell transformation. We believe that a better understanding on mechanisms employed by Tax will provide basic information on human T-cell transformation processes and may reveal new therapeutic targets for the treatment of T-cell leukemia/lymphoma. ? ?
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