The human T-cell leukemia virus type I (HTLV-I) is an onco-retrovirus that infects and transforms human CD4 T cells in vitro and in vivo. HTLV-I is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), an aggressive and invariably fatal hematological disease. The virus is transmitted through sexual contact, contaminated blood and mother-to-child by breastfeeding, and is present in 20-30 million people worldwide. HTLV-I-mediated T-cell transformation arises from a multi-step oncogenic process in which the virus induces chronic T-cell proliferation, resulting in accumulation of genetic defects and deregulated cell growth. It is not yet fully understood how HTLV-I engenders ATLL, but the virus blocks the apoptotic network and expends the proliferative capacity of infected cells. HTLV-I infects and immortalizes primary human T cells in vitro and, after several months, these cells acquire the ability to grow in the absence of interleukin-2, referred to as transformation. We previously demonstrated that the viral oncogenic Tax can reactivate telomerase expression, an event required for long-term proliferation of HTLV-I-transformed cells in vitro and in vivo. This application will investigate the molecular events associated with deregulated telomerase activity and its role in the HTLV-I transformation process. Since telomerase reactivation represents one of the central steps in human carcinogenesis, results from this study will have broad application beyond viral oncogenesis.
HTLV-I is associated with the development of an aggressive form of lymphocytic leukemia known as adult T- cell leukemia/lymphoma (ATLL). Although many features of HTLV-I biology have been discovered, the disease has no cure. Reactivation of telomerase activity is an essential step in the expansion and survival of HTLV-I- transformed cells in patients. Understanding the mechanisms involved in reactivation of telomerase activity by HTLV-I may uncover novel targets for the treatment of ATLL.
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