The HTLV-1 HBZ Oncoprotein and Its Role in Adult T-Cell Leukemia/Lymphoma

Human T-cell leukemia virus-1 (HTLV-1) is the etiological agent of a series of chronic inflammatory diseases such as HTLV-associated myelopathy/Tropical spastic paraparesis (HAM/TSP), uveitis, dermatitis, and pneumonitis, and, importantly, of a T-cell lymphoproliferative neoplasm designed adult T-cell leukemia/lymphoma (ATL). Two viral proteins, Tax-1 and HBZ, are crucially involved in HTLV-1 infectivity and in ATL by altering key pathways of cell homeostasis. A fundamental distinction between the expression of the two oncoproteins exists, witnessed by the fact that Tax-1 is expressed in early phases of HTLV-1 infectivity and ATL onset but may be lost in a substantial number of established ATL, whereas HBZ is always expressed in all phases of HTLV-1 infection and in all ATL. Additionally, while Tax-1 can be localized both in the cytoplasm and nucleus in all cases of disease, recent evidence indicate that HBZ is localized solely in the cytoplasm in cells of HTLV-1-infected individuals, asymptomatic carriers (AC) and patients suffering from HAM/TSP. Importantly, ATL instead marks a progressive dislocation of HBZ in the nucleus. Thus, both the expression and the subcellular localization of HBZ represent distinctive elements in the process of HTLV-1-associated pathology. Within this frame, recent studies point to a very important involvement of HBZ in disarranging the homeostasis of the cell not only at the transcriptional but most importantly at the post-transcriptional level as a result of the interaction with crucial factors regulating RNA splicing and stability. These recent aspects of the HBZ biology will be discussed for their implication in HTLV-1-mediated oncogenesis.