Abstract
The human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus causing an aggressive T-cell malignancy, adult T-cell leukemia (ATL). Although HTLV-1 has a compact RNA genome, it has evolved elaborate mechanisms to maximize its coding potential. The structural proteins Gag, Pro, and Pol are encoded in the unspliced form of viral mRNA, whereas the Env protein is encoded in singly spliced viral mRNA. Regulatory and accessory proteins, such as Tax, Rex, p30II, p12, and p13, are translated only from fully spliced mRNA. For effective viral replication, translation from all forms of HTLV-1 transcripts has to be achieved in concert, although unspliced mRNA are extremely unstable in mammalian cells. It has been well recognized that HTLV-1 Rex enhances the stability of unspliced and singly spliced HTLV-1 mRNA by promoting nuclear export and thereby removing them from the splicing site. Rex specifically binds to the highly structured Rex responsive element (RxRE) located at the 3′ end of all HTLV-1 mRNA. Rex then binds to the cellular nuclear exporter, CRM1, via its nuclear export signal domain and the Rex–viral transcript complex is selectively exported from the nucleus to the cytoplasm for effective translation of the viral proteins. Yet, the mechanisms by which Rex inhibits the cellular splicing machinery and utilizes the cellular pathways beneficial to viral survival in the host cell have not been fully explored. Furthermore, physiological impacts of Rex against homeostasis of the host cell via interactions with numerous cellular proteins have been largely left uninvestigated. In this review, we focus on the biological importance of HTLV-1 Rex in the HTLV-1 life cycle by following the historical path in the literature concerning this viral post-transcriptional regulator from its discovery to this day. In addition, for future studies, we discuss recently discovered aspects of HTLV-1 Rex as a post-transcriptional regulator and its use in host cellular pathways.
Highlights
Human T-cell leukemia virus type 1 (HTLV-1) is widely accepted as the causative agent of adult T-cell leukemia (ATL) and was discovered almost a decade after the recognition of ATL as a disease (Takatsuki, 2005)
It was confirmed that adult T-cell leukemia virus (ATLV) and human T-cell lymphotropic virus (HTLV)-1 were the same virus and the description was modified thereafter to indicate that ATL is caused by HTLV-1 (Popovic et al, 1982, 1983)
HTLV-1 Rex is a major post-transcriptional regulator of viral expression, which is responsible for active viral replication in the early phase of infection and for reduction of viral activity to establish latency in the late phase of infection
Summary
Human T-cell leukemia virus type 1 (HTLV-1) is widely accepted as the causative agent of adult T-cell leukemia (ATL) and was discovered almost a decade after the recognition of ATL as a disease (Takatsuki, 2005). RNA viruses have evolved elegant mechanisms to maximize coding potential and to precisely regulate the expression of encoded genes. Overlapping reading frames, internal ribosome entry sites, alternative splicing, sub-optimal Kozak sequences, and ribosomal frame shifting are among the varied mechanisms used to maximize genomic coding potential and regulate expression of specific viral genes (Balvay et al, 2007). HTLV-1 encodes more than 10 open reading frames (ORFs) by employing several mechanisms to achieve appropriate and ordered expression of these genes, including alternative splicing and programmed ribosomal frame-shifting (PRF). PRF is a mechanism frequently used by viruses to alter the translational reading frame by shifting the ribosome at a slippery site (Theis et al, 2008). Unspliced HTLV-1 RNA yields Gag, Pro, and Pol proteins and the singly spliced RNA produces Env, whereas the functional proteins derived from the pX region can be translated only from doubly spliced mRNA
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