Abstract
Human T-lymphotropic virus 1 (HTLV-1) was the first human retrovirus to be discovered and is the causative agent of adult T-cell leukemia/lymphoma (ATL) and the neurodegenerative disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The importance of microRNA (miRNA) in the replicative cycle of several other viruses, as well as in the progression of associated pathologies, has been well established in the past decade. Moreover, involvement of miRNA alteration in the HTLV-1 life cycle, and in the progression of its related oncogenic and neurodegenerative diseases, has recently come to light. Several HTLV-1 derived proteins alter transcription factor functionalities, interact with chromatin remodelers, or manipulate components of the RNA interference (RNAi) machinery, thereby establishing various routes by which miRNA expression can be up- or down-regulated in the host cell. Furthermore, the mechanism of action through which dysregulation of host miRNAs affects HTLV-1 infected cells can vary substantially and include mRNA silencing via the RNA-induced silencing complex (RISC), transcriptional gene silencing, inhibition of RNAi components, and chromatin remodeling. These miRNA-induced changes can lead to increased cell survival, invasiveness, proliferation, and differentiation, as well as allow for viral latency. While many recent studies have successfully implicated miRNAs in the life cycle and pathogenesis of HTLV-1 infections, there are still significant outstanding questions to be addressed. Here we will review recent discoveries elucidating HTLV-1 mediated manipulation of host cell miRNA profiles and examine the impact on pathogenesis, as well as explore future lines of inquiry that could increase understanding in this field of study.
Highlights
Human T-lymphotropic virus 1 (HTLV-1) was discovered in the early 1980s by two-independent groups working in the United States (Poiesz et al, 1980, 1981) and Japan (Yoshida et al, 1982)
The interaction of Tax with CRE Binding Protein (CREB) occurs in order to bind to cis-acting replication element (CRE) enhancer sequences on the viral promoter, which is a critical step in viral transactivation and in the formation of the pre-initiation complex (Kwok et al, 1996; Giebler et al, 1997; Kashanchi et al, 1998; Wu et al, 2004; Easley et al, 2010)
Due to the diverse cellular pathways controlled by miRNAs, the hijacking of the RNA interference (RNAi) molecular machinery and alteration of host miRNA profiles represents a significant and diverse mechanism by which viruses can progress through their life cycle and effect varied disease states in the host organism
Summary
Human T-lymphotropic virus 1 (HTLV-1) was discovered in the early 1980s by two-independent groups working in the United States (Poiesz et al, 1980, 1981) and Japan (Yoshida et al, 1982). There are currently four known types of HTLV, HTLV-1 is by far the most pathogenic of the group and has the distinction of being the first oncogenic retrovirus discovered in humans (Mahieux and Gessain, 2007) It infects an estimated 15–20 million people worldwide and has been implicated as the causative agent in a number of disease conditions, most notably adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Several studies have demonstrated that HTLV-1 alters the profile of host miRNAs (Bellon et al, 2009; Rahman et al, 2012) Examining these findings regarding HTLV-1 and miRNA in connection with the recent discoveries of miRNA manipulation by other retroviruses demonstrates the importance of the RNA interference (RNAi) machinery to these related viral infections. The findings detailed here have significantly transformed our understanding of the life cycle of the HTLV-1 virus and provide new avenues for scientific exploration and therapeutic intervention against this pathogen
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