Abstract
Human T-lymphotrophic virus type 1 (HTLV-1) and Bovine leukemia virus (BLV) belong to the Deltaretrovirus genus. HTLV-1 is the etiologic agent of the highly aggressive and currently incurable cancer adult T-cell leukemia (ATL) and a neurological disease HTLV-1-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). BLV causes neoplastic proliferation of B cells in cattle: enzootic bovine leucosis (EBL). Despite the severity of these conditions, infection by HTLV-1 and BLV appear in most cases clinically asymptomatic. These viruses can undergo latency in their hosts. The silencing of proviral gene expression and maintenance of latency are central for the establishment of persistent infection, as well as for pathogenesis in vivo. In this review, we will present the mechanisms that control proviral activation and retroviral latency in deltaretroviruses, in comparison with other exogenous retroviruses. The 5′ long terminal repeats (5′-LTRs) play a main role in controlling viral gene expression. While the regulation of transcription initiation is a major mechanism of silencing, we discuss topics that include (i) the epigenetic control of the provirus, (ii) the cis-elements present in the LTR, (iii) enhancers with cell-type specific regulatory functions, (iv) the role of virally-encoded transactivator proteins, (v) the role of repressors in transcription and silencing, (vi) the effect of hormonal signaling, (vii) implications of LTR variability on transcription and latency, and (viii) the regulatory role of non-coding RNAs. Finally, we discuss how a better understanding of these mechanisms may allow for the development of more effective treatments against Deltaretroviruses.
Highlights
The first reported human retrovirus and the representative of the Deltaretrovirus genus isHuman T-lymphotrophic virus type 1 (HTLV-1), the etiologic agent of adult T-cell leukemia (ATL)and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) [1]
We summarize current knowledge on viral and host processes involved in the regulation of deltaretrovirus transcription and latency, including, (i) epigenetic control of the provirus, (ii) the cis-elements present in the long terminal repeats (LTRs), (iii) enhancers with cell-type specific regulatory functions, (iv) the role virally-encoded transactivator proteins, (v) the role repressors in transcription and silencing processes, (vi) the effect of hormonal signaling, (vii) implications of LTR variability on transcription and latency, and (viii) the regulatory role of non-coding RNAs
293T cells mediate repression of Human immunodeficiency virus (HIV)-1 transcription through two mechanisms: (1) activating enhancer binding protein (AP)-4 bound to the 30 E-box can block binding of TATA binding protein (TBP) to TATA box in LTR promoter, and (2) Activating enhancer binding protein 4 (AP-4) can mediate the recruitment of HDAC1 to the LTR in vivo [175,176,177]
Summary
The first reported human retrovirus and the representative of the Deltaretrovirus genus is. Intracellular signaling pathways activate the main regulatory elements in the 50 LTR: Tax-response element (TRE-1, -2, -3) enhancers that interact with the cellular transcription factors CREB/ATF [32,33,34] These complexes have been identified in cells isolated ex vivo from HTLV-1 carriers or BLV-infected sheep [34,35]. These data indicate that both viral and host cellular factors play important roles in deltaretrovirus silencing. The cell type and its differentiation state with respect to variety of cell activation signals may lead to substantial variations in transcriptional activity of a LTR depending on the chromatin context [42] All these variables generate a remarkably wide range of levels for viral gene expression. We discuss how these integrated mechanisms contribute towards maintenance or release from viral latency in the context of antiviral therapeutics
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