The long-term goals of this project are to better understand the pathogenicity of HTLV-1 in order to develop more effective therapeutic therapies. The short term objectives of this proposal are to demonstrate that the viral genes Tax and HBZ are critical for divergent HTLV-1C replication and immune escape in vivo. The inability of the host immune defenses to efficiently eliminate HTLV-1C Tax and HBZ expressing cells results in higher proviral loads and inflammation. This project will investigate viral events associated with inflammation and lung disease. This research proposal is significant because infection with HTLV-1 is associated with fatal diseases; there are no curative treatments, few treatment options and a very poor overall 4-year survival rate. In addition, sexually transmitted diseases like HTLV-1 can spread beyond isolated populations and increase the risks of HTLV-1C spreading worldwide. The research conducted will for the first time shed light on HTLV-1C infection and replication in vivo using a rabbit model. HTLV-1C infection in central Australia exceeds 40% among indigenous adults living in remote areas, and as much as 30% of these individuals have diseases attributed to HTLV-1 infection. This project will have a positive health impact by providing a better understanding of HTLV-1C biology and pathogenesis and aid in the future development of therapeutics to prevent HTLV-1-associated diseases. This project is innovative in that it will use the first and only HTLV-1C infectious molecular clone developed in my laboratory to study in vivo HTLV-1C virus infectivity and replication. None of these experiments have been done before due to the lack of an HTLV-1C molecular clone. Sequence analyses have revealed that both Tax and HBZ immunodominant epitopes are mutated in all HTLV-1C sequences published to date. In turn, we believe that this will prevent host immune clearance of infected cells leading to a higher proviral load and increased inflammation. Understanding the molecular mechanisms involved may offer new therapeutic targets for the treatment of HTLV-1 diseases.