Human T-cell Leukemia Virus type 1 (HTLV-1) is the etiologic agent of a fatal form of leukemia and a progressive neurodegenerative disease and is also linked to a spectrum of immunoinflammatory disorders. These diseases arise from infected T-cells undergoing pathogenic reprogramming in response to complex virus-mediated processes that are not yet fully understood. To date, HTLV-1-associated diseases have proven to be highly refractory to a wide array of therapeutic strategies. Recently, however, a molecularly targeted therapy showed promise for some HTLV-1 leukemia patients. This observation highlights the importance of devising therapeutic approaches that disrupt or exploit specific viral processes as a means of sensitizing infected cells for elimination or rendering them innocuous. Considering this goal, we have focused on characterizing functions of the viral protein, HTLV-1 basic leucine zipper (bZIP) factor (HBZ), which is implicated in pathogenic reprogramming of infected cells. HBZ localizes to the nucleus and affects transcription. It contains an N-terminal activation domain that binds the homologous cellular coactivators, p300 and CBP, and a C-terminal bZIP domain. Through the leucine zipper (ZIP) sub-domain, HBZ is able to dimerize with a subset of cellular bZIP transcription factors. These interactions generally block the cellular factors from binding DNA and activating transcription. This effect is consistent with the current view that HBZ does not bind to DNA due to its lack of certain amino acid motifs normally found in other bZIP factors. Despite this property, HBZ is frequently involved in activating gene expression, but how it does so remains largely unresolved. The preliminary data in this application show that HBZ binds to a group of cellular bZIP transcription factors known as small Mafs (sMafs). Strikingly, the HBZ/sMaf complex displays DNA-binding activity. These observations led to the hypothesis that HBZ/sMaf heterodimers recognize specific DNA sequences and, through HBZ-mediated recruitment of p300/CBP, activate transcription. The objective of Specific Aim 1 is to characterize HBZ/sMaf/DNA complexes. The preliminary data in this application also define HMOX1 as a gene that is specifically activated by HBZ/sMaf complexes. HMOX1 produces heme oxygenase- 1, an enzyme that modulates cellular detoxification events such as the elimination of reactive oxygen species (ROS). This function may play a role in the survival of HTLV-1-infected cells, as the activities of other viral proteins trigger production of ROS that, in turn, can induce apoptosis. These observations support the hypothesis that elevated HMOX1 expression in infected cells reduces oxidative stress caused by other viral proteins and exposure to chemotherapeutic agents. The objective of Specific Aim 2 is to determine whether inhibition of HMOX1 activity deters the survival and proliferation of HTLV-1-infected T-cells. Results from these studies will elucidate a novel mechanism used by HBZ to activate certain cellular genes. This information will be useful for advancing molecularly targeted approaches against HTLV-1-associated diseases.
The complex retrovirus, Human T-cell Leukemia Virus type 1 (HTLV-1), causes a fatal malignancy known as adult T-cell leukemia (ATL) and a progressive neurological disorder known as HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). While there is currently no standard treatment or cure for these diseases, recent promising results have been obtained using a therapeutic approach that specifically targets molecular processes directly related to the HTLV-1 infection. The goal of this project is to characterize functions of the HTLV-1-encoded protein, HBZ, which is believed to play a key role in HTLV-1-mediated pathogenesis. Thus, the information obtained from this project will serve as the foundation for designing effective treatments for patients suffering from ATL and HAM/TSP.
