153 Molecular pathogenesis by HTLV-1 bZIP factor

Human T-cell leukemia virus type 1 (HTLV-1) mainly transmits by cell-to-cell contact. Therefore, this virus induces proliferation of infected cells to facilitate transmission. In HTLV-1 infected individuals, infected cells proliferate in vivo. This proliferation of infected cells leads to the development of adult T-cell leukemia (ATL) and inflammatory diseases including HTLV-1 associated myelopathy (HAM). HTLV-1 bZIP factor (HBZ) is consistently expressed in ATL cells and HTLV-1 infected cells, and plays a critical role in their proliferation. Transgenic expression of HBZ causes T-cell lymphoma and inflammatory diseases, indicating that HBZ is critical for the pathogenesis of HTLV-1. We analyzed the function of HBZ and found that it possessed opposite functions to Tax in many pathways. We found that Tax could activate the classical Wnt pathway while HBZ inhibited it by interacting with TCF1/LEF1. The canonical Wnt pathway is activated in the thymus, and its transcription factors, TCF1/LEF1, suppressed the viral gene transcription by Tax. Conversely, the canonical Wnt pathway is suppressed in the peripheral T cells in which the non-canonical Wnt pathway is activated. HBZ enhanced the expression of Wnt5a, which is a ligand in non-canonical Wnt signaling. Knockdown of Wnt5a suppressed the proliferation and migration of ATL cells. Thus, activation of the non-canonical Wnt pathway by HBZ is linked with proliferation of ATL cells. These findings suggest that HTLV-1 is adapted to, not thymic T cells, but peripheral T cells. HBZ modulates the intracellular environment suitable for HTLV-1 replication and proliferation of infected cells.