scholarly journals Human T-lymphotropic Virus Type 1-infected Cells Secrete Exosomes That Contain Tax Protein

2014 ◽  
Vol 289 (32) ◽  
pp. 22284-22305 ◽  
Author(s):  
Elizabeth Jaworski ◽  
Aarthi Narayanan ◽  
Rachel Van Duyne ◽  
Shabana Shabbeer-Meyering ◽  
Sergey Iordanskiy ◽  
...  
Keyword(s):  
Virus Type ◽  
T Lymphotropic Virus ◽  
Tax Protein ◽  
Infected Cells

scholarly journals Differential Expression of Nur77 Family Members in Human T-Lymphotropic Virus Type 1-Infected Cells: Transactivation of theTR3/nur77 Gene by Tax Protein

1998 ◽  
Vol 72 (8) ◽  
pp. 6902-6906 ◽  
Author(s):  
Xiaolin Chen ◽  
Vladimir Zachar ◽  
Chawnshang Chang ◽  
Peter Ebbesen ◽  
Xiangdong Liu
Keyword(s):  
Differential Expression ◽  
Virus Type ◽  
Luciferase Reporter ◽  
Binding Motif ◽  
Luciferase Reporter Gene ◽  
Functional Protein ◽  
T Lymphotropic Virus ◽  
Tax Protein ◽  
Infected Cells

ABSTRACT We analyzed the differential expression and regulation of three members of the Nur77 transcription factor family by the human T-lymphotropic virus type 1 (HTLV-1) Tax protein. We have demonstrated that in both HTLV-1-infected cells and Tax-expressing JPX-9 cells,TR3/nur77 is highly expressed, whereas neitherNOR-1 nor NOT expression is detectable. Transient transfection analysis further confirmed the Tax transactivation of the TR3/nur77 promoter but not theNOR-1 promoter in different cell types. Furthermore, expression of a luciferase reporter gene driven by the NGFI-B (rat homolog of TR3/Nur77) response element (NBRE) provided evidence that Tax-mediated transactivation resulted in the induction of a functional protein. Cotransfection assays with the TR3/nur77 promoter sequence or the NBRE binding motif together with a series of Tax mutants have shown that Tax-induced TR3/nur77 expression is mediated by CREB/ATF-related transcription factors.

Relevance of CREB phosphorylation in the anti-apoptotic function of human T-lymphotropic virus type 1 tax protein in serum-deprived murine fibroblasts

2004 ◽  
Vol 299 (1) ◽  
pp. 57-67 ◽  
Author(s):  
Roberta Trevisan ◽  
Laura Daprai ◽  
Lidia Acquasaliente ◽  
Vincenzo Ciminale ◽  
Luigi Chieco-Bianchi ◽  
...  
Keyword(s):  
Virus Type ◽  
Creb Phosphorylation ◽  
T Lymphotropic Virus ◽  
Tax Protein ◽  
Murine Fibroblasts

scholarly journals Human T-Lymphotropic Virus Type 1 Tax Protein Complexes with P-TEFb and Competes for Brd4 and 7SK snRNP/HEXIM1 Binding

2010 ◽  
Vol 84 (24) ◽  
pp. 12801-12809 ◽  
Author(s):  
Won-Kyung Cho ◽  
Moon Kyoo Jang ◽  
Keven Huang ◽  
Cynthia A. Pise-Masison ◽  
John N. Brady
Keyword(s):  
Molecular Weight ◽  
Rna Polymerase Ii ◽  
Virus Type ◽  
T Lymphotropic Virus ◽  
Cyclin T1 ◽  
Tax Protein ◽  
In Cells

ABSTRACT Positive transcription elongation factor b (P-TEFb) plays an important role in stimulating RNA polymerase II elongation for viral and cellular gene expression. P-TEFb is found in cells in either an active, low-molecular-weight (LMW) form or an inactive, high-molecular-weight (HMW) form. We report here that human T-lymphotropic virus type 1 (HTLV-1) Tax interacts with the cyclin T1 subunit of P-TEFb, forming a distinct Tax/P-TEFb LMW complex. We demonstrate that Tax can play a role in regulating the amount of HMW complex present in the cell by decreasing the binding of 7SK snRNP/HEXIM1 to P-TEFb. This is seen both in vitro using purified Tax protein and in vivo in cells transduced with Tax expression constructs. Further, we find that a peptide of cyclin T1 spanning the Tax binding domain inhibits the ability of Tax to disrupt HMW P-TEFb complexes. These results suggest that the direct interaction of Tax with cyclin T1 can dissociate P-TEFb from the P-TEFb/7SK snRNP/HEXIM1 complex for activation of the viral long terminal repeat (LTR). We also show that Tax competes with Brd4 for P-TEFb binding. Chromatin immunoprecipitation (ChIP) assays demonstrated that Brd4 and P-TEFb are associated with the basal HTLV-1 LTR, while Tax and P-TEFb are associated with the activated template. Furthermore, the knockdown of Brd4 by small interfering RNA (siRNA) activates the HTLV-1 LTR promoter, which results in an increase in viral expression and production. Our studies have identified Tax as a regulator of P-TEFb that is capable of affecting the balance between its association with the large inactive complex and the small active complex.

scholarly journals Transcriptome and Somatic Mutation Associated with Non-Malignant Human T Lymphotropic Virus Type 1 Infection and Adult T-Cell Leukemia/Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2843-2843
Author(s):  
Huseini Hatimbhai Kagdi ◽  
Graham Phillip Taylor
Keyword(s):  
T Cell ◽  
Virus Type ◽  
Antisense Transcript ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
T Lymphotropic Virus ◽  
Adult T Cell Leukemia ◽  
Human Genes ◽  
Infected Cells

Abstract Aggressive Adult T-cell leukemia/lymphoma (ATL), a human T lymphotropic virus type 1 (HTLV-1) -associated disease, has a poor prognosis. There is an urgent need for effective prevention and treatment. A large number of genomic aberrations including hundreds of somatic mutations and copy number changes are typically observed in ATL tumours, with certain genes, PLCG1, PRKCB, CCR4, CARD11, STAT3, TP53, VAV1, TBL1XR1, NOTCH1, GATA3 and IRF4 mutated in over 10% of cases(1). CD4+CCR4+CD26-CD7- is the dominant immunophenotype of lymphocytes in patients with ATL (ATL cells) but infected cells with similar immunophenotype ('ATL-like' cells) are also present in patients with non-malignant HTLV-1 infection(2, 3). Aggressive ATL develops in patients with non-malignant HTLV-1 (asymptomatic carriers (AC) and patients with HTLV-1 associated myelopathy (HAM)) over decades with evolution from high proviral load (PVL) and non-dominant clonal growth through emergence of dominant clones and indolent to aggressive ATL. HTLV-1 infected clones have been shown to have cells with mixed immunophenotype. The aim was to investigate specific genomic aberration associated with non-malignant HTLV-1 infection, dominant clonal growth and ATL. RNA sequencing followed by differential gene expression and mutational analysis of HTLV-1 and human genes was performed on sorted CD4+CCR4+CD26-CD7- cells from nine patients with ATL (four with indolent, four with aggressive ATL and one with indolent to aggressive transformation; ATL cells); and 18 patients with high PVL non-malignant HTLV-1 infection (three with dominant clones and 15 with non-dominant clones, 'ATL-like' infected cells). Seven antisense transcript of HTLV-1 genome was detected. A spliced antisense transcript spanning the whole HTLV-1 genome was detected in all samples whilst two novel transcripts were detected in > 2 samples. There was no significant difference in viral transcriptome expression between ATL and 'ATL-like' cells. A total of 13637 including 7952 well annotated human genes were detected within which 400 genes were significantly differentially expressed ( > 2 fold change and false discover rate < 0.1) between ATL and 'ATL-like' cells as shown in figure 1. Small nuclear RNA and endothelial cancer associated genes were upregulated in patients with ATL whilst T-cell, inflammatory, apoptosis and proliferation related genes were upregulated in patients with non-malignant HTLV-1 infection respectively. Principle component analysis did not showed any significant cluster but hierarchical analysis using differentially expressed genes showed clustering of ATL cells from patient with aggressive ATL, indolent ATL and 'ATL-like' cells from patients with non-malignant HTLV-1 infection (AC and HAM) of ATL as shown in figure 2. One out of three patient with high PVL non-malignant HTLV-1 infection and dominant clones (HKU) clustered with ATL and this patient progressed to ATL 12 months from sample data. Hallmark pathway analysis showed upregulation cluster in 'ATL-like' cells with only metabolism associated pathways clustered in ATL cells as shown in table 1. Expression of all recurrently mutated genes was detected and mutation analysis is currently underway. In summary, there is a major overlap of infected cell transcriptome in patient with non-malignant HTLV-1 infection and ATL. ATL cells have downregulation of T-cell, inflammatory, apoptosis and proliferation related genes compared to 'ATL-like' infected cells whilst upregulation of small nuclear RNAs. Transcriptome analysis in patient with high PVL non-malignant HTLV-1 infection might help in further prognostication in malignant risk.Kataoka K, Nagata Y, Kitanaka A, Shiraishi Y, Shimamura T, Yasunaga J, et al. Integrated molecular analysis of adult T cell leukemia/lymphoma. Nature genetics. 2015;47(11):1304-15.Kagdi H, Demontis MA, Ramos JC, Taylor GP. Switching and loss of cellular cytokine producing capacity characterize in vivo viral infection and malignant transformation in human T- lymphotropic virus type 1 infection. PLoS pathogens. 2018;14(2):e1006861.Kagdi HH, Demontis MA, Fields PA, Ramos JC, Bangham CR, Taylor GP. Risk stratification of adult T-cell leukemia/lymphoma using immunophenotyping. Cancer medicine. 2017;6(1):298-309. Disclosures No relevant conflicts of interest to declare.

scholarly journals Transactivation of the human interleukin-6 gene by human T-lymphotropic virus type 1 Tax protein

Blood ◽  
1994 ◽  
Vol 84 (5) ◽  
pp. 1573-1578 ◽  
Author(s):  
I Yamashita ◽  
S Katamine ◽  
R Moriuchi ◽  
Y Nakamura ◽  
T Miyamoto ◽  
...  
Keyword(s):  
Virus Type ◽  
Interleukin 6 ◽  
Molecular Mechanisms ◽  
Constitutive Expression ◽  
Cell Types ◽  
Nf Kappa B ◽  
T Lymphotropic Virus ◽  
Tax Protein ◽  
T Cell Lines

Abstract Interleukin-6 (IL-6) is a multifunctional cytokine that regulates both humoral and cellular immune responses. Accumulating evidence suggests that the infection of T cells and other cell types with human T- lymphotropic virus type 1 (HTLV-1) results in the constitutive expression of IL-6. However, the underlying molecular mechanisms are little understood. When a reporter plasmid, pIL6-CAT-E3, in which the human IL-6 enhancer/promoter region from -630 to +14 was linked to the bacterial chloramphenicol acetyltransferase (CAT) gene, was transfected, HTLV-1-infected but not -uninfected T-cell lines activated the IL-6 promoter. This indicated the presence of a factor transactivating the IL-6 gene in the infected cells. To evaluate the involvement of the HTLV-1-encoded transacting factor (Tax) in this transactivation, we examined the effect of transient cotransfection with the Tax-expression plasmid, pMAX-Neo, on the transcription from the IL-6 promoter by use of COS1 cells. The cotransfected COS1 has about six-times greater the CAT activity than that transfected with pIL6-CAT-E3 alone. The analysis of a series of deletions of the IL-6 promoter suggested that the region (-105/-47) containing a NF kappa B site was crucial for the Tax responsiveness. We further examined the effect of Tax on endogenous IL-6 gene expression using the Jurkat clone, JPX-9, stably transfected with pMAX-Neo. JPX-9 accumulated steady state transcripts of the endogenous IL-6 gene in response to the induction of Tax expression. Our findings indicate an important role of the Tax protein in the expression of IL-6 in cells infected with HTLV-1.

Inhibition of Apoptosis by Human T-Lymphotropic Virus Type-1 Tax Protein

2003 ◽  
Vol 1010 (1) ◽  
pp. 591-597 ◽  
Author(s):  
DANIELA SAGGIORO ◽  
LIDIA ACQUASALIENTE ◽  
LAURA DAPRAI ◽  
LUIGI CHIECO-BIANCHI
Keyword(s):  
Virus Type ◽  
T Lymphotropic Virus ◽  
Tax Protein

scholarly journals The Human T-Lymphotropic Virus Type 1 Tax Protein Inhibits Nonsense-Mediated mRNA Decay by Interacting with INT6/EIF3E and UPF1

2012 ◽  
Vol 86 (14) ◽  
pp. 7530-7543 ◽  
Author(s):  
V. Mocquet ◽  
J. Neusiedler ◽  
F. Rende ◽  
D. Cluet ◽  
J.-P. Robin ◽  
...  
Keyword(s):  
Virus Type ◽  
Mrna Decay ◽  
T Lymphotropic Virus ◽  
Tax Protein ◽  
Nonsense Mediated Mrna Decay

scholarly journals Cellular Immune Responses against Simian T-Lymphotropic Virus Type 1 Target Tax in Infected Baboons

2016 ◽  
Vol 90 (11) ◽  
pp. 5280-5291 ◽  
Author(s):  
Iris Castro ◽  
Teresa M. Giret ◽  
Diogo M. Magnani ◽  
Helen S. Maxwell ◽  
Oliver Umland ◽  
...  
Keyword(s):  
Immune Responses ◽  
Virus Type ◽  
T Cell Response ◽  
Content Type ◽  
T Lymphotropic Virus ◽  
Cellular Immune Responses ◽  
Tax Protein ◽  
Baboon Model ◽  
Cellular Immune

ABSTRACTThere are currently 5 million to 10 million human T-lymphotropic virus type 1 (HTLV-1)-infected people, and many of them will develop severe complications resulting from this infection. A vaccine is urgently needed in areas where HTLV-1 is endemic. Many vaccines are best tested in nonhuman primate animal models. As a first step in designing an effective HTLV-1 vaccine, we defined the CD8+and CD4+T cell response against simian T-lymphotropic virus type 1 (STLV-1), a virus closely related to HTLV-1, in olive baboons (Papioanubis). Consistent with persistent antigenic exposure, we observed that STLV-1-specific CD8+T cells displayed an effector memory phenotype and usually expressed CD107a, gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α). To assess the viral targets of the cellular immune response in STLV-1-infected animals, we used intracellular cytokine staining to detect responses against overlapping peptides covering the entire STLV-1 proteome. Our results show that, similarly to humans, the baboon CD8+T cell response narrowly targeted the Tax protein. Our findings suggest that the STLV-1-infected baboon model may recapitulate some of the important aspects of the human response against HTLV-1 and could be an important tool for the development of immune-based therapy and prophylaxis.IMPORTANCEHTLV-1 infection can lead to many different and often fatal conditions. A vaccine deployed in areas of high prevalence might reduce the incidence of HTLV-1-induced disease. Unfortunately, there are very few animal models of HTLV-1 infection useful for testing vaccine approaches. Here we describe cellular immune responses in baboons against a closely related virus, STLV-1. We show for the first time that the immune response against STLV-1 in naturally infected baboons is largely directed against the Tax protein. Similar findings in humans and the sequence similarity between the human and baboon viruses suggest that the STLV-1-infected baboon model might be useful for developing a vaccine against HTLV-1.

scholarly journals Transcriptional activation of human TR3/nur77 gene expression by human T-lymphotropic virus type I Tax protein through two AP-1-like elements

1999 ◽  
Vol 80 (12) ◽  
pp. 3073-3081 ◽  
Author(s):  
Xiangdong Liu ◽  
Xiaolin Chen ◽  
Vladimir Zachar ◽  
Chawnshang Chang ◽  
Peter Ebbesen
Keyword(s):  
Transcription Factor ◽  
Virus Type ◽  
Transcriptional Activation ◽  
Gene Deletion ◽  
Type I ◽  
Transcription Start ◽  
T Lymphotropic Virus ◽  
Tax Protein ◽  
Infected Cells ◽  
Mutation Analyses

The Tax transactivator of human T-lymphotropic virus type I (HTLV-I) is capable of inducing expression of the human immediate-early TR3/nur77 gene. Deletion and mutation analyses of the TR3/nur77 promoter demonstrated that multiple transcription elements in the 121 bp sequence proximal to the transcription start site are required for full Tax transactivation. Mutations of CArG-like, Ets and RCE motifs in this region severely decreased Tax transactivation. Mutation of either of the two identical AP-1-like elements (NAP 1 and 2) immediately upstream of the TATA box caused around 80% reduction of Tax transactivation. Mutation of both NAP elements blocked Tax-mediated activation totally. These two NAP elements could confer Tax-responsiveness on a heterologous basal promoter. Furthermore, the specific NAP-binding complex was only observed in HTLV-I-infected cells. Formation of this specific NAP-binding complex was correlated directly with Tax expression, as demonstrated in JPX-9 cells upon induction of Tax expression. The specific NAP binding could be competed for by consensus AP-1 and CREB elements, indicating that the NAP-binding proteins probably belong to the AP-1 and CREB/ATF transcription factor families. Supershift analysis with antibodies to both the AP-1 and CREB/ATF transcription factor families revealed that only anti-JunD antibody could partially shift this NAP-binding complex, indicating that JunD is a component of the NAP complex. This work suggests that JunD is involved in Tax-regulated TR3/nur77 expression.

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