Role of viral HBZ in HTLV-1 replication and pathogenesis

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DESCRIPTION (provided by applicant): It is estimated that approximately 15 to 25 million people worldwide are infected with human T-cell leukemia virus type 1 (HTLV-1). HTLV-1 infection is associated primarily with leukemia and neurological disease in a small percentage of infected patients. Although infected patients develop antibody and cytotoxic Tlymphocyte (CTL) responses to many of the viral proteins, the virus manages to persist throughout life. One of the viral regulatory proteins, Tax, is critical for viral transcription and replication and has been clearly implicated in T-lymphocyte transformation in vitro and oncogenesis in vivo. An HTLV-1 protein termed HBZ, encoded by the anti-sense strand of the proviral genome has been described. Over expression studies have shown that HBZ is a nuclear b-ZIP protein that down regulates Tax induced HTLV-1 viral transcription by hetero-dimerizing with CREB-2 and other b-ZIP proteins of the AP-1 complex. The functional role of HBZ in the context of a replicating virus and its contribution to viral replication and viral-induced cellular Immortalization / transformation in vitro and on viral replication kinetics in vivo has yet to be tested. Two specific aims are proposed to test the hypothesis that HBZ contributes to the regulatory balance of HTLV-1 gene transcription potentially disrupting viral replication and cell transformation in vitro and ultimately the ability of the virus to persist in an animal model. These studies will determine for the first time the contribution of HBZ to HTLV-1 biology and pathogenesis. These studies could ultimately provide a means for therapeutic targeting of this protein to eradicate HTLV-1 persistent infection in the host.