Human T-cell Leukemia Virus type 1 (HTLV-1) is a complex retrovirus that primarily infects CD4+ T- cells in vivo. HTLV-1 infection is associated with diverse pathological effects, including a fatal form of leukemia and a progressive neurodegenerative disease. As these diseases have proven refractory to numerous therapeutic approaches, current clinical treatments show limited efficacy. Separately, certain aspects of HTLV- 1 biology have hindered the development of a vaccine. One relatively untested approach that may overcome these obstacles is to inhibit the infectious spread of HTLV-1 within the host's T-cell population as a means of reducing the risk of disease development and viral transmission. Central to the development of novel therapies based on this concept is a thorough understanding of the HTLV-1 infection process. HTLV-1 infection between T-cells requires the infected and target cells to come into direct contact. This event triggers polarization of the microtubule organizing center in the infected cell towards the target cell, allowing the HTLV-1 envelope glycoprotein (Env) and other viral structural proteins to translocate to the cell-cell juncture. While Env is central to infection, mechanisms modulating its intracellular trafficking before and during cell-contact-mediated infection are relatively unclear. We recently discovered that the HTLV-1-encoded transcriptional regulator, HBZ, augments infection. We believe this function stems from effects of HBZ on the expression of certain cellular genes that participate in the infection process. Accordingly, we recently found that HBZ activates MYOF transcription. This cellular gene encodes myoferlin, which functions in membrane sorting and plays an important role in endosomal trafficking. Our preliminary data indicate that HBZ activates myoferlin expression by recruiting the cellular coactivator, p300/CBP, to the MYOF gene. Consistent with HBZ-mediated activation, myoferlin is aberrantly expressed in HTLV-1-infected T-cells. Importantly, reduced expression or functional inhibition of myoferlin in these cells inhibits viral infection and diminishes the level of Env. Based on these preliminary data and data from other studies, we hypothesize that myoferlin promotes the trafficking of Env through an endosomal pathway that favors the availability of Env for viral assembly. Without myoferlin, we hypothesize that Env is routed to lysosomes for degradation. We propose to address these hypotheses in Specific Aim 1 in which we will characterize how myoferlin affects Env trafficking in HTLV-1-infected T-cells. Results from this aim will clarify a regulatory mechanism of Env intracellular trafficking that is central to viral infection. Focusing on HBZ- mediated activation of MYOF transcription, we hypothesize that specific compounds that block the interaction between HBZ and p300/CBP will reduce myoferlin expression and, in turn, viral infection. We propose to test this hypothesis in Specific Aim 2 in which we will identify compounds that block the interaction. For HTLV-1 carriers and patients alike, results from this aim will identify compounds with potential therapeutic capabilities.