Activation of HTLV-I long terminal repeat by apoptosis inducing agents: Mechanism and implications for HTLV-I pathogenicity (Review)

Schavinsky-Khrapunsky, Yana; Gold, Evgenia; Ben-Aroya, Zahi; Torgeman, Amram; Aboud, Mordechai; Huleihel, Mahmoud

doi:10.3892/ijmm.11.1.3

Cited by 6 publications

(7 citation statements)

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“…Strikingly, most of the described cell stress conditions known to stimulate HTLV-1 mRNA transcription and translation are also predicted to reduce cap-dependent translation initiation (1, 2, 79-81). Thus, it is plausible that under stress conditions known to activate both HTLV-1 mRNA synthesis and viral protein expression (72,73), translation initiation of the full-length HTLV-1 mRNA occurs via a cap-independent mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…A number of studies suggest that cellular stress conditions and cellular stress response mechanisms are capable of activating latent HTLV-1 by stimulating LTR-induced transcription of viral mRNA (72,73). Upon HTLV-1 activation, the viral accessory proteins p13 participates in the maintenance and further stimulation of a cellular stress environment required for HTLV-1 replication (74).…”

Section: Discussionmentioning

confidence: 99%

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The 5′ Untranslated Region of the Human T-Cell Lymphotropic Virus Type 1 mRNA Enables Cap-Independent Translation Initiation

Olivares

Landry

Cáceres

et al. 2014

J Virol

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The human T-cell leukemia virus type 1 (HTLV-1) is a complex human retrovirus that causes adult T cell leukemia and of HTLVassociated myelopathy/tropical spastic paraparesis. The mRNA of some complex retroviruses, including the human and simian immunodeficiency viruses (HIV and SIV), can initiate translation using a canonical cap-dependent mechanism or through an internal ribosome entry site (IRES). In this study, we present strong evidence showing that like HIV-1 and SIV, the 5=-untranslated region (5=UTR) of the HTLV-1 full-length mRNA harbors an IRES. Cap-independent translational activity was evaluated and demonstrated using dual luciferase bicistronic mRNAs in rabbit reticulocyte lysate, in mammalian cell culture, and in Xenopus laevis oocytes. Characterization of the HTLV-1 IRES shows that its activity is dependent on the ribosomal protein S25 (RPS25) and that its function is highly sensitive to the drug edeine. Together, these findings suggest that the 5=UTR of the HTLV-1 full-length mRNA enables internal recruitment of the eukaryotic translation initiation complex. However, the recognition of the initiation codon requires ribosome scanning. These results suggest that, after internal recruitment by the HTLV-1 IRES, a scanning step takes place for the 40S ribosomal subunit to be positioned at the translation initiation codon. IMPORTANCEThe mechanism by which retroviral mRNAs recruit the 40S ribosomal subunit internally is not understood. This study provides new insights into the mechanism of translation initiation used by the human T-cell lymphotropic virus type 1 (HTLV-1). The results show that the HTLV-1 mRNA can initiate translation via a noncanonical mechanism mediated by an internal ribosome entry site (IRES). This study also provides evidence showing the involvement of cellular proteins in HTLV-1 IRES-mediated translation initiation. Together, the data presented in this report significantly contribute to the understanding of HTLV-1 gene expression.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The 5′ Untranslated Region of the Human T-Cell Lymphotropic Virus Type 1 mRNA Enables Cap-Independent Translation Initiation

Olivares

Landry

Cáceres

et al. 2014

J Virol

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“…In contrast to Tax and Rex, which are encoded by a bicistronic pX mRNA formed by double splicing of the viral RNA [21,34,35], the other four accessory proteins are encoded by different pX mRNAs formed by alternative splicing events [33,36]. Pique et al [37] have detected CTL activity in HTLV-I infected individuals against specific peptides from each of these ORF I and ORF II proteins, indicating that each of them is produced natural human infections.…”

Section: Introductionmentioning

confidence: 99%

Role of Tax protein in human T-cell leukemia virus type-I leukemogenicity

Azran

Schavinsky-Khrapunsky

Aboud

2004

Retrovirology

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139

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HTLV-1 is the etiological agent of adult T-cell leukemia (ATL), the neurological syndrome TSP/ HAM and certain other clinical disorders. The viral Tax protein is considered to play a central role in the process leading to ATL. Tax modulates the expression of many viral and cellular genes through the CREB/ATF-, SRF-and NF-κB-associated pathways. In addition, Tax employs the CBP/ p300 and p/CAF co-activators for implementing the full transcriptional activation competence of each of these pathways. Tax also affects the function of various other regulatory proteins by direct protein-protein interaction. Through these activities Tax sets the infected T-cells into continuous uncontrolled replication and destabilizes their genome by interfering with the function of telomerase and topoisomerase-I and by inhibiting DNA repair. Furthermore, Tax prevents cell cycle arrest and apoptosis that would otherwise be induced by the unrepaired DNA damage and enables, thereby, accumulation of mutations that can contribute to the leukemogenic process. Together, these capacities render Tax highly oncogenic as reflected by its ability to transform rodent fibroblasts and primary human T-cells and to induce tumors in transgenic mice. In this article we discuss these effects of Tax and their apparent contribution to the HTLV-1 associated leukemogenic process. Notably, however, shortly after infection the virus enters into a latent state, in which viral gene expression is low in most of the HTLV-1 carriers' infected T-cells and so is the level of Tax protein, although rare infected cells may still display high viral RNA. This low Tax level is evidently insufficient for exerting its multiple oncogenic effects. Therefore, we propose that the latent virus must be activated, at least temporarily, in order to elevate Tax to its effective level and that during this transient activation state the infected cells may acquire some oncogenic mutations which can enable them to further progress towards ATL even if the activated virus is re-suppressed after a while. We conclude this review by outlining an hypothetical flow of events from the initial virus infection up to the ultimate ATL development and comment on the risk factors leading to ATL development in some people and to TSP/HAM in others.

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“…Rex is a 27 kD, nucleolar-localizing phosphoprotein that functions to enhance nuclear export of unspliced or singly spliced viral RNA thus contributing to virus propagation19 -23. Both Tax and Rex have been the subject of recent reviews [15][16][17]19,[24][25][26][27] . In this review we focus on the important role that accessory proteins have in HTLV-1 replication and pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Role of accessory proteins of HTLV-1 in viral replication, T cell activation, and cellular gene expression

Michael¹

2004

Front Biosci

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Human T-cell lymphotropic virus type 1 (HTLV-1), causes adult T cell leukemia/lymphoma (ATLL), and initiates a variety of immune mediated disorders. The viral genome encodes common structural and enzymatic proteins characteristic of all retroviruses and utilizes alternative splicing and alternate codon usage to make several regulatory and accessory proteins encoded in the pX region (pX ORF I to IV). Recent studies indicate that the accessory proteins p12I, p27I, p13II, and p30II, encoded by pX ORF I and II, contribute to viral replication and the ability of the virus to maintain typical in vivo expression levels. Proviral clones that are mutated in either pX ORF I or II, while fully competent in cell culture, are severely limited in their replicative capacity in a rabbit model. These HTLV-1 accessory proteins are critical for establishment of viral infectivity, enhance T-lymphocyte activation and potentially alter gene transcription and mitochondrial function. HTLV-1 pX ORF I expression is critical to the viral infectivity in resting primary lymphocytes suggesting a role for the calcineurin-binding protein p12I in lymphocyte activation. The endoplasmic reticulum and cis-Golgi localizing p12I activates NFAT, a key T cell transcription factor, through calcium-mediated signaling pathways and may lower the threshold of lymphocyte activation via the JAK/STAT pathway. In contrast p30II localizes to the nucleus and represses viral promoter activity, but may regulate cellular gene expression through p300/CBP or related co-activators of transcription. The mitochondrial localizing p13II induces morphologic changes in the organelle and may influence energy metabolism infected cells. Future studies of the molecular details HTLV-1 "accessory" proteins interactions will provide important new directions for investigations of HTLV-1 and related viruses associated with lymphoproliferative diseases. Thus, the accessory proteins of HTLV-1, once thought to be dispensable for viral replication, have proven to be directly involved in viral spread in vivo and represent potential targets for therapeutic intervention against HTLV-1 infection and disease.

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Activation of HTLV-I long terminal repeat by apoptosis inducing agents: Mechanism and implications for HTLV-I pathogenicity (Review)

Cited by 6 publications

References 0 publications

The 5′ Untranslated Region of the Human T-Cell Lymphotropic Virus Type 1 mRNA Enables Cap-Independent Translation Initiation

The 5′ Untranslated Region of the Human T-Cell Lymphotropic Virus Type 1 mRNA Enables Cap-Independent Translation Initiation

Role of Tax protein in human T-cell leukemia virus type-I leukemogenicity

Role of accessory proteins of HTLV-1 in viral replication, T cell activation, and cellular gene expression

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