Human T-cell lymphotropic virus type 1 and its oncogenesis

Abstract

Human T-cell lymphotropic virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma (ATL), a rapidly progressing clonal malignancy of CD4+ T lymphocytes. Exploring the host-HTLV-1 interactions and the molecular mechanisms underlying HTLV-1-mediated tumorigenesis is critical for developing efficient therapies against the viral infection and associated leukemia/lymphoma. It has been demonstrated to date that several HTLV-1 proteins play key roles in the cellular transformation and immortalization of infected T lymphocytes. Of note, the HTLV-1 oncoprotein Tax inhibits the innate IFN response through interaction with MAVS, STING and RIP1, causing the suppression of TBK1-mediated phosphorylation of IRF3/IRF7. The HTLV-1 protein HBZ disrupts genomic integrity and inhibits apoptosis and autophagy of the target cells. Furthermore, it is revealed that HBZ enhances the proliferation of ATL cells and facilitates evasion of the infected cells from immunosurveillance. These studies provide insights into the molecular mechanisms by which HTLV-1 mediates the formation of cancer as well as useful strategies for the development of new therapeutic interventions against ATL. In this article, we review the recent advances in the understanding of the pathogenesis, the underlying mechanisms, clinical diagnosis and treatment of the disease caused by HTLV-1 infection. In addition, we discuss the future direction for targeting HTLV-1-associated cancers and strategies against HTLV-1.

Figure 1

Schematic representation of HTLV-1 and HTLV-2/3/4 genomes. p19 and p24 are the major core proteins of HTLVs. Gray: LTR, Long Terminal Repeat; Coding regions for all major proteins: gag, group-specific antigen; pro, protease; pol, polymerase; env, envelope; rex, regulator of expression; tax, transactivator; HBZ, HTLV basic leucine zipper. The pink letters indicate the positions of the major proteins encoded by the corresponding genes, including the MA (matrix), CA (capsid), NC (nucleocapsid) proteins of gag, the PR (protease), RT (reverse transcriptase), IN (integrase) enzymes of pol and the SU (surface) and TM (transmembrane) proteins of env.