Strategies of Human T-Cell Leukemia Virus Type 1 for Persistent Infection: Implications for Leukemogenesis of Adult T-Cell Leukemia-Lymphoma

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) establishes persistent infection in vivo in two distinct ways: de novo infection and clonal proliferation of infected cells. Two viral genes, Tax and HTLV-1 bZIP factor (HBZ) play critical roles in viral transcription and promotion of T-cell proliferation, respectively. Tax is a potent transactivator not only for viral transcription but also for many cellular oncogenic pathways, such as the NF-κB pathway. HBZ is a suppressor of viral transcription and has the potential to change the immunophenotype of infected cells, conferring an effector regulatory T cell (eTreg)like signature (CD4+ CD25+ CCR4+ TIGIT+ Foxp3+) and enhancing the proliferation of this subset. Reports that mice transgenic for either gene develop malignant tumors suggest that both Tax and HBZ are involved in leukemogenesis by HTLV-1. However, the immunogenicity of Tax is very high, and its expression is generally suppressed in vivo. Recently, it was found that Tax can be expressed transiently in a small subpopulation of adult T-cell leukemia-lymphoma (ATL) cells and plays a critical role in maintenance of the overall population. HBZ is expressed in almost all infected cells except for the rare Tax-expressing cells, and activates the pathways associated with cell proliferation. These findings indicate that HTLV-1 fine-tunes the expression of viral genes to control the mode of viral propagation. The interplay between Tax and HBZ is the basis of a sophisticated strategy to evade host immune surveillance and increase transmissionand can lead to ATL as a byproduct.

Progress on Ras/MAPK Signaling Research and Targeting in Blood and Solid Cancers

“…However, it is suggested that Tax dependence is only required early during infection as Tax1 is rarely detected in the leukemic cells of ATL patients [228,231]. Tax1 is the HTLV-1 viral, trans-activator protein that has pleiotropic effects in activating and dysregulating cellular processes involved in growth and immunosurveillance and has been extensively studied regarding its activities as a tumor initiator in ATL [233,234]. Tax1 overexpression performed in cancer cell lines (breast, colon, and hepatoma) resulted in increased proliferation as quantified by MTT assay [235].…”

HTLV-1 Infection and Pathogenesis: New Insights from Cellular and Animal Models

“…HTLV-1-infected T cell lines have also been established from ATL patients, such as ATL-2 cells, MT-1, ATL-T, TLOm1, ED, ATL35-T, and ATL-55T. Commonly used cell lines in HTLV studies are listed in Table 1 [ 11 , 26 , 27 , 28 , 29 , 30 , 31 ].…”

“…The HTLV-1-transformed cell lines (e.g., MT-4, C8166, HUT-102, and M-T2), ATL-derived cells (e.g., F6T, K3T, S1T, and Su9T01) or transiently transfected cells (e.g., Jurkat, HEK293, HeLa cells) are the common cell models used to investigate the role of Tax and HBZ in cell signaling deregulation [ 11 , 28 ]. NF-κB is one of the most extensively studied pathways deregulated by Tax and HBZ, and the Tax activation of the NF-κB pathway is well established as a critical step in the onset of T-cell transformation and development of ATL [ 68 , 69 , 70 ] ( Figure 3 ).…”

“…Besides being the etiological agent of adult T-cell leukemia/lymphoma (ATL), in 3–5% of infected subjects, HTLV-1 causes immune hypersensitivity conditions like arthritis, uveitis, and most importantly, the HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a fatal chronic inflammatory neurological disorder [ 5 , 6 , 7 , 8 ]. Most infected people, however, remain asymptomatic, highlighting the role of the immune system in the control of infection [ 9 , 10 , 11 ]. Worldwide, more than 20 million subjects are infected by HTLV and, despite advances in treatment, patients with aggressive ATL generally have a poor prognosis [ 12 , 13 ].…”

Comprehensive high-throughput meta-analysis of differentially expressed microRNAs in transcriptomic datasets reveals significant disruption of MAPK/JNK signal transduction pathway in Adult T-cell leukemia/lymphoma

“…A subpopulation of individuals infected with HTLV-1 (6% of male and of 2% female subjects) develop Adult T-cell leukemia/lymphoma (ATLL) after a long latency period of 4 to 6 decades [ 3 , 4 ]. ATLL is a malignant T-cell neoplasm characterized by pleomorphic leukemic cells with hyper segmented nuclei, which are immunophenotypically comparable to regulatory T-cells [ 5 ]. This aggressive peripheral T-cell malignancy is associated with a poor prognosis and numerous clinical complications, such as hypercalcemia and immunodeficiency [ 4 ].…”