Abstract
Human T-cell leukemia virus type 1 (HTLV-1) was the first retrovirus to be discovered as a causative agent of adult T-cell leukemia-lymphoma (ATL) and chronic inflammatory diseases. Two viral factors, Tax and HTLV-1 bZIP factor (HBZ), are thought to be involved in the leukemogenesis of ATL. Tax expression is frequently lost due to DNA methylation in the promoter region, genetic changes to the tax gene, and deletion of the 5′ long terminal repeat (LTR) in approximately half of all ATL cases. On the other hand, HBZ is expressed in all ATL cases. HBZ is known to function in both protein form and mRNA form, and both forms play an important role in the oncogenic process of HTLV-1. HBZ protein has a variety of functions, including the suppression of apoptosis, the promotion of proliferation, and the impairment of anti-viral activity, through the interaction with several host cellular proteins including p300/CBP, Foxp3, and Foxo3a. These functions dramatically modify the transcriptional profiling of host T cells. HBZ mRNA also promotes T cell proliferation and viability. HBZ changes infected T cells to CCR4+TIGIT+CD4+ effector/memory T cells. This unique immunophenotype enables T cells to migrate into various organs and tissues and to survive in vivo. In this review, we summarize how HBZ hijacks the transcriptional networks and immune systems of host T cells to contribute to HTLV-1 pathogenesis on the basis of recent new findings about HBZ and tax.
Highlights
The burden of viral infection in cancer is high, with estimates having more than 20% of cancer cases caused by infection (Bouvard et al, 2009)
HTLV-1 bZIP factor (HBZ) increases the number of induced Treg cells, in which Foxp3 expression is unstable, and converts them to Foxp3− T cells with increased interferon-γ production (Yamamoto-Taguchi et al, 2013). These results suggest that HBZ induces Foxp3+ T cells but hijacks their transcriptional network, which leads to inflammatory disease in the host
These studies suggest that Human T-cell leukemia virus type 1 (HTLV-1) might influence earlier stages of hematopoietic cell differentiation and induce infected hematopoietic stem cells (HSCs) or other infected progenitor cells to abnormally differentiate into CD4+ Treg-like cells
Summary
The burden of viral infection in cancer is high, with estimates having more than 20% of cancer cases caused by infection (Bouvard et al, 2009). Thereafter, HTLV-1 was found to be a causative agent of adult T-cell leukemia-lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) (Hinuma et al, 1981; Gessain et al, 1985; Gallo, 2005). HTLV-1 increases its copy number primarily by triggering the proliferation of infected cells to facilitate its transmission (Etoh et al, 1997; Cavrois et al, 1998). These properties distinguish HTLV-1 from another well-known human retrovirus, human immunodeficiency virus type 1 (HIV-1). Unlike HIV-1, HTLV-1 can infect a variety of cell types, but more than 90% of infected cells are CD4+ memory T cells in vivo (Richardson et al, 1990; Rizkallah et al, 2017)
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