Clonal expansion of HTLV-1 positive CD8+ cells relies on cIAP-2 but not on c-FLIP expression

Zane, Linda; Sibon, David; Legras, Catherine; Lachuer, Joël; Wierinckx, Anne; Mehlen, Patrick; Delfau‐Larue, Marie‐Hélène; Gessain, Antoine; Gout, Olivier; Pinatel, Christiane; Lançon, Agnès; Mortreux, Franck; Wattel, Éric

doi:10.1016/j.virol.2010.07.023

Cited by 17 publications

(20 citation statements)

References 57 publications

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“…Furthermore, Tax activates the transcription of miR130b (33) and miR146a (32), and downregulates miR149 and miR873, which both directly target the chromatin-remodeling factors p300 and p/CAF that are known to play a critical role in HTLV-1 pathogenesis (47). Nonimmortalized HTLV-1-positive clones express a wide range of Tax RNA levels, likely modifying numerous cellular pathways (5)(6)(7)(8). Here, we found no relationship between Tax and miRNA expression in these cells.…”

Section: Discussioncontrasting

confidence: 52%

“…2A; refs. [5][6][7][8]. Figure 2B shows that a significant positive correlation linked HBZ to miRNA expression for miR17, miR21, miR23b, and miR27b in CD4 þ T cells.…”

Section: Resultsmentioning

confidence: 92%

“…In vivo, HTLV-1 preferentially infects both CD4 þ and CD8 þ T cells, and triggers the persistent clonal expansion of these two host cell subsets, although cellular transformation is often restricted to the CD4 þ subset (5). Although ATLL occurs in only 1% to 3% of infected individuals, the nonimmortalized infected CD4 þ T cells derived from carriers without malignancy accumulate numerous preleukemic features, including multinuclearity, impaired cytokinesis, chromatin bridges, suboptimal telomerase activity, and increased cell proliferation (6)(7)(8). In contrast, the clonal expansion of infected CD8 þ T cells was found to rely on delayed cell death in a cIAP-2-dependent manner (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

“…Genome-wide transcriptome reprogramming is a hallmark of HTLV-1 infection (5,8,9) that relies mainly on Tax and HBZ, two HTLV-1-encoded proteins that can hijack host transcription factors and chromatin modifiers to positively or negatively modulate cellular gene expression (10,11). The pleiotropic effects of Tax activity include cell proliferation, prevention of apoptosis, and promotion of genetic instability (12).…”

Section: Introductionmentioning

confidence: 99%

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HTLV-1 bZIP Factor HBZ Promotes Cell Proliferation and Genetic Instability by Activating OncomiRs

et al. 2014

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Viruses disrupt the host cell microRNA (miRNA) network to facilitate their replication. Human T-cell leukemia virus type I (HTLV-1) replication relies on the clonal expansion of its host CD4 þ and CD8 þ T cells, yet this virus causes adult T-cell leukemia/lymphoma (ATLL) that typically has a CD4 þ phenotype. The viral oncoprotein Tax, which is rarely expressed in ATLL cells, has long been recognized for its involvement in tumor initiation by promoting cell proliferation, genetic instability, and miRNA dysregulation. Meanwhile, HBZ is expressed in both untransformed infected cells and ATLL cells and is involved in sustaining cell proliferation and silencing virus expression. Here, we show that an HBZ-miRNA axis promotes cell proliferation and genetic instability, as indicated by comet assays that showed increased numbers of DNA-strand breaks. Expression profiling of miRNA revealed that infected CD4 þ cells, but not CD8 þ T cells, overexpressed oncogenic miRNAs, including miR17 and miR21. HBZ activated these miRNAs via a posttranscriptional mechanism. These effects were alleviated by knocking down miR21 or miR17 and by ectopic expression of OBFC2A, a DNA-damage factor that is downregulated by miR17 and miR21 in HTLV-1-infected CD4 þ T cells. These findings extend the oncogenic potential of HBZ and suggest that viral expression might be involved in the remarkable genetic instability of ATLL cells. Cancer Res; 74(21); 6082-93. Ó2014 AACR.

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Section: Discussioncontrasting

confidence: 52%

“…2A; refs. [5][6][7][8]. Figure 2B shows that a significant positive correlation linked HBZ to miRNA expression for miR17, miR21, miR23b, and miR27b in CD4 þ T cells.…”

Section: Resultsmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HTLV-1 bZIP Factor HBZ Promotes Cell Proliferation and Genetic Instability by Activating OncomiRs

et al. 2014

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“…The percentage of transfection reached 40-50%. Tax knockdown was performed using lentiviral short hairpin RNA (shRNA) anti-Tax cloned in pKLO vector, as reported previously (32). Briefly, infected T cell line HUT102 was treated as follows: cell medium was changed 1 h before treatment, and cells were plated in a U-bottom 96-well plate.…”

Section: Tax and Crmp2 Expressionmentioning

confidence: 99%

Human T Lymphotropic Virus Type 1 Increases T Lymphocyte Migration by Recruiting the Cytoskeleton Organizer CRMP2

Varrin‐Doyer

Nicolle

Marignier

et al. 2012

The Journal of Immunology

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Recruitment of virus-infected T lymphocytes into the CNS is an essential step in the development of virus-associated neuroinflammatory diseases, notably myelopathy induced by retrovirus human T leukemia virus-1 (HTLV-1). We have recently shown the key role of collapsin response mediator protein 2 (CRMP2), a phosphoprotein involved in cytoskeleton rearrangement, in the control of human lymphocyte migration and in brain targeting in animal models of virus-induced neuroinflammation. Using lymphocytes cloned from infected patients and chronically infected T cells, we found that HTLV-1 affects CRMP2 activity, resulting in an increased migratory potential. Elevated CRMP2 expression accompanies a higher phosphorylation level of CRMP2 and its more pronounced adhesion to tubulin and actin. CRMP2 forms, a full length and a shorter, cleaved one, are also affected. Tax transfection and extinction strategies show the involvement of this viral protein in enhanced full-length and active CRMP2, resulting in prominent migratory rate. A role for other viral proteins in CRMP2 phosphorylation is suspected. Full-length CRMP2 confers a migratory advantage possibly by preempting the negative effect of short CRMP2 we observe on T lymphocyte migration. In addition, HTLV-1–induced migration seems, in part, supported by the ability of infected cell to increase the proteosomal degradation of short CRMP2. Finally, gene expression in CD69+ cells selected from patients suggests that HTLV-1 has the capacity to influence the CRMP2/PI3K/Akt axis thus to positively control cytoskeleton organization and lymphocyte migration. Our data provide an additional clue to understanding the infiltration of HTLV-1–infected lymphocytes into various tissues and suggest that the regulation of CRMP2 activity by virus infection is a novel aspect of neuroinflammation.

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Curcumin increased the expression of c‐FLIP in HTLV‐1‐associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients

Poursina

Mohammadi

Yazdi

et al. 2019

J of Cellular Biochemistry

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Human T‐cell lymphotropic virus type 1 (HTLV‐1)‐associated myelopathy/tropical spastic paraparesis (HAM/TSP) disease is a chronic neuroinflammatory disease, which is associated with HTLV‐1 infection. There is no effective and satisfactory treatment of HAM/TSP. It has been shown that curcumin exhibits modulatory effects on apoptosis and cytotoxicity‐related molecules in HAM/TSP patients. In the present study, we examined the effect of curcumin on the gene expression of caspase‐8, caspase‐10, and anti‐apoptotic protein c‐FLIP, in HAM/TSP patients. Furthermore, we compared the expression of these molecules between HAM/TSP and asymptomatic carriers. Real‐time PCR was performed to examine the mRNA expression of caspase‐8, caspase‐10, and c‐FLIP in studied groups. The mRNA expression of caspase‐8 and caspase‐10 was similar before and after curcumin treatment in HAM/TSP patients (P > 0.05). The mRNA expression of c‐FLIPL and c‐FLIPs was higher after curcumin treatment compared with before treatment and significant differences were observed between the two groups (P = 0.004 and P = 0.044, respectively). The mRNA expression levels of caspase‐8, caspase‐10, c‐FLIPL, and c‐FLIPs were not statistically significant between HAM/TSP patients and asymptomatic carriers (P < 0.05). In conclusion, our results showed that curcumin increased the expression of c‐FLIP in HAM/TSP patients which might suggest that, this molecule is involved in the apoptosis of HTLV‐1‐infected cells. Further studies with large sample size could be useful to clarify the role of this supplement in HAM/TSP patients.

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Clonal expansion of HTLV-1 positive CD8+ cells relies on cIAP-2 but not on c-FLIP expression

Cited by 17 publications

References 57 publications

HTLV-1 bZIP Factor HBZ Promotes Cell Proliferation and Genetic Instability by Activating OncomiRs

HTLV-1 bZIP Factor HBZ Promotes Cell Proliferation and Genetic Instability by Activating OncomiRs

Human T Lymphotropic Virus Type 1 Increases T Lymphocyte Migration by Recruiting the Cytoskeleton Organizer CRMP2

Curcumin increased the expression of c‐FLIP in HTLV‐1‐associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients

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