Role of viral APH-2 in HTLV-2 replication and persistence

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DESCRIPTION (provided by applicant): Human T-cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) are human tumorigenic retroviruses that encode the Tax viral oncogene, plus a newly identified possible secondary oncogene encoded by the antisense strand of the viral genome. While ~ 15 to 25 million people are infected with HTLV-1 or HTLV-2, a small portion fall victim to disease. HTLV-1 infected people eventually develop leukemia or immune mediated disease, whereas HTLV-2 disease is rare, but some infected subjects present with lymphoproliferative and neurological symptoms. Although infected individuals develop antibody and cytotoxic T-lymphocyte (CTL) responses to many of the viral proteins, the virus manages to persist throughout life. One of the viral encoded proteins, Tax, is critical for viral transcriptio and replication and has been implicated in the T-cell transformation process. Transcription from the antisense strand of the HTLV-1 genome has been described by us and others and the encoded protein termed HBZ has been shown to reduce Tax-mediated viral transcription, promote the proliferation of HTLV-1 infected cells by altering the transcriptional activity of multiple cellular factors, and be required for viral persistence in vivo. HBZ, originally thought t be unique to HTLV-1 has been hypothesized to play a role in pathogenesis. Recently, an anti-sense HTLV-2 protein (AHP-2) with limited homology to HBZ has been identified. The functional role of APH-2 in the context of a replicating virus has yet to be tested. We seek to test the hypothesis that APH-2 contributes to the balance of HTLV-2 gene transcription potentially disrupting viral replication and cell transformation in vitro and ultimately the ability of the virs to persist in an animal model. Specifically, we will determine 1) the role of APH-2 on HTLV-2 replication and T- lymphocyte transformation 2) and the effects of APH-2 on viral persistence in vivo by examining viral replication kinetics and immune response in inoculated rabbits. Importantly, since HTLV-1 and HTLV-2 are closely related retroviruses, but have distinct etiological roles in human disease, comparative studies on anti- sense proteins of HTLV-1 and HTLV-2 will provide fundamental insights into their distinct pathogenic properties. This R21 is a necessary first step to ultimately analyze the hypothesis that the anti-sense proteins in HTLV-1 and HTLV-2 affect distinct cellular factors/pathways, which determines the differences in their pathogenesis and comparative functional studies will provide important insight as to their potential as targets for therapy. PUBLIC HEALTH RELEVANCE: Approximately 15 to 25 million people worldwide are infected with human T-cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2). Although the viral Tax is the key oncogene it has become clear that persistence and pathogenesis requires contributions of other viral genes. Here we focus on a novel identified viral gene encoded by the antisense strand of the HTLV-2 genome, termed APH-2. Understanding the role APH-2 in HTLV-2 replication and persistence/latent infection will have significant implications for therapeutic targeting of these proteins and understanding how retroviruses utilize antisense encoded proteins.