Abstract
Human T-cell leukemia virus type 1 (HTLV-1), the first reported human oncogenic retrovirus, is the etiologic agent of highly aggressive, currently incurable diseases such as adult T-cell leukemia–lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 proteins, including Tax and HBZ, have been shown to have critical roles in HTLV-1 pathogenicity, yet the underlying mechanisms of HTLV-1-driven leukemogenesis are unclear. The frequent disruption of genetic and epigenetic gene regulation in various types of malignancy, including ATL, is evident. In this review, we illustrate a focused range of topics about the establishment of HTLV-1 memory: (1) genetic lesion in the Tax interactome pathway, (2) gene regulatory loop/switch, (3) disordered chromatin regulation, (4) epigenetic lock by the modulation of epigenetic factors, (5) the loss of gene fine-tuner microRNA, and (6) the alteration of chromatin regulation by HTLV-1 integration. We discuss the persistent influence of Tax-dependent epigenetic changes even after the disappearance of HTLV-1 gene expression due to the viral escape from the immune system, which is a remaining challenge in HTLV-1 research. The summarized evidence and conceptualized description may provide a better understanding of HTLV-1-mediated cellular transformation and the potential therapeutic strategies to combat HTLV-1-associated diseases.
Highlights
Human T-cell leukemia virus type 1 (HTLV-1) infection (Poiesz et al, 1980; Hinuma et al, 1981; Yoshida et al, 1982) is associated with the development of adult T-cell leukemia–lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), most virus carriers remain asymptomatic throughout their lifespan
Considering the low rate of incidence, clinical observation implies that HTLV-1 lacks a strong capacity to induce leukemogenesis, in contrast to other animal leukemia viruses
A highly immunogenic protein, is not expressed in most aggressive-type ATL cases because HTLV-1 provirus is substantially silenced by proviral defect and/or an epigenetic mechanism (Tamiya et al, 1996; Koiwa et al, 2002; Taniguchi et al, 2005)
Summary
Human T-cell leukemia virus type 1 (HTLV-1) infection (Poiesz et al, 1980; Hinuma et al, 1981; Yoshida et al, 1982) is associated with the development of adult T-cell leukemia–lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), most virus carriers remain asymptomatic throughout their lifespan. A highly immunogenic protein, is not expressed in most aggressive-type ATL cases because HTLV-1 provirus is substantially silenced by proviral defect and/or an epigenetic mechanism (Tamiya et al, 1996; Koiwa et al, 2002; Taniguchi et al, 2005). The reason for this seemingly paradoxical observation is yet to be determined, it is suggested that the acquired cellular characteristics, including promoting cell proliferation and apoptotic resistance, is conferred by viral genes in early-phase infected cells and by genetic/epigenetic abnormalities in latephase, highly malignant ATL cells (Figure 1). Tax has already disappeared at the time of ATL onset, Tax and its interactome (described in later chapters) have already left multiple genetic and epigenetic memories, contributing ATL onset This switch during leukemogenesis is supported by transcriptome data; the changes in gene expression in infected cells are dominated by disordered homeostasis and the characteristics of ATL. We introduce a hypothesis with important implications that might explain the underlying mechanism of the issue: the molecular memories inherited from HTLV-1
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