scholarly journals The Roles of AMP-Activated Protein Kinase-Related Kinase 5 as a Novel Therapeutic Target of Human T-Cell Leukaemia Virus Type 1-Infected T-Cells

10.5772/52541 ◽  
2013 ◽  
Author(s):  
Mariko Tomita
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protein Kinase ◽  
Therapeutic Target ◽  
Cell Leukaemia ◽  
Leukaemia Virus ◽  
Human T Cell ◽  
Amp Activated Protein Kinase ◽  
Novel Therapeutic

AB0268 HUMAN T-CELL LEUKAEMIA VIRUS TYPE 1 MAY INVALIDATE T-SPOT.TB RESULTS AMONG RHEUMATOID ARTHRITIS PATIENTS: A RETROSPECTIVE OBSERVATIONAL STUDY

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1432.1-1433
Author(s):  
K. Umekita ◽  
Y. Hashiba ◽  
R. Kudou ◽  
S. Miyauchi ◽  
M. Kimura ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Type ◽  
Peripheral Blood ◽  
Medical Records ◽  
Cell Leukaemia ◽  
Leukaemia Virus ◽  
Human T Cell ◽  
Ifn Γ

Background:In clinical rheumatology, interferon-γ release assays (IGRAs) have been reported as a useful diagnostic test for latent tuberculosis infection (LTBI) before beginning the administration of biologics such as anti-TNF therapies (1). CD4-positive T cells are the main target in Human T-cell leukaemia virus type 1 (HTLV-1) infection. Several reports suggest that the reaction of tuberculin skin test (TST) is attenuated in HTLV-1-positive individuals compared with that in HTLV-1-negative individuals (2). However, it remains unclear whether IGRAs are reliable for detecting TB infection among HTLV-1-positive RA patients.Objectives:The present study aimed to investigate the usefulness of the T-SPOT.TBassay in HTLV-1-positive RA patients. In addition, the association between the existence of IFN-γ producing T cells and HTLV-1 proviral loads (PVLs) in HTLV-1-positive RA patients was analysed on the basis of the T-SPOT.TBassay results.Methods:We reviewed the medical records of 75 HTLV-1-negative and 29 HTLV-1-positive RA patients were suspected cases of LTBI and evaluated using the T-SPOT.TBassay as a clinical practice from April 2012 to July 2019. The results of T-SPOT.TBwere collected from medical records, retrospectively. Peripheral blood samples were obtained from HTLV-1-positive RA patients for the analysis of HTLV-1 PVLs values. The study protocol was approved by the research ethics committees of our hospitals.Results:Approximately 55% of the HTLV-1-positive RA patients showed invalid results for the T-SPOT.TBassay (p < 0.0001); the cause of invalid results was a spot-forming count of >10 spots in the negative controls of the T-SPOT.TBassay among HTLV-1-positive RA patients. Among HTLV-1-positive RA patients, HTLV-1 PVL values were significantly higher in 16 patients who showed invalid results than in 13 patients who did not (p = 0.003). There were no between-group differences in female patient ratio, age, RA disease activity and therapeutic regimens. IFN-γ producing cells were detected in the peripheral blood of HTLV-1-positive RA patients without stimulation with TB-specific antigens.Conclusion:The incidence of invalid results for the T-SPOT.TBassay has been reported to be as low as 0.6% (3). The results of this assay for screening of LTBI in HTLV-1-positive RA patients should be interpreted with caution. Furthermore, our results show that an increase in IFN-γ producing T cell numbers due to HTLV-1 infection in RA patients may affect the pathogenesis of RA.References:[1]Iannone, F., et al.J. Rheumatol. Suppl.91, 41-46 (2014).[2]Tachibana, N., et al.Int. J. Cancer42, 829-831 (1988).[3]Rego, K., et al.Tuberculosis (Edinb.)108, 178-185 (2018).Acknowledgments:We would like to thank Dr Yuki Hashikura and Ms Yuki Kaseda of the University of Miyazaki for their technical support in this work. We would also like to acknowledge Ms Yumiko Kai at the Institute of Rheumatology, Zenjinkai Shimin-no-Mori Hospital, for her help in data management.A part this work was supported by a grant from the Practical Research Project for Rare/Intractable Diseases of the Japan Agency for Medical Research and Development (Grant No. JP19ek0109356), a Health and Labor Sciences Research Grant on Rare and Intractable Diseases from the Ministry of Health, Labor and Welfare of Japan (Grant No. 19FC1007), and a Grant-in-Aid for Clinical Research from Miyazaki University Hospital.Disclosure of Interests:Kunihiko Umekita Paid instructor for: Astellas Pharma Inc. Chugai Pharma Inc. Tanabe-Mitsubishi Pharma Inc., Speakers bureau: Bristol-Myers Squibb, Yayoi Hashiba: None declared, Risa Kudou: None declared, Shunichi Miyauchi: None declared, Masatoshi Kimura: None declared, Motohiro Matsuda: None declared, Chihiro Iwao: None declared, Yumi Kariya: None declared, Takeshi Kawaguchi: None declared, Katoko Takajo: None declared, Koushou Iwao: None declared, Yuuki Rikitake: None declared, Ichiro Takajo: None declared, Toshihiko Hidaka Paid instructor for: Astellas Pharma Inc. Chugai Pharma Inc. Tanabe-Mitsubishi Pharma Inc., Speakers bureau: Astellas Pharma Inc. Chugai Pharma Inc. Tanabe-Mitsubishi Pharma Inc., Akihiko Okayama: None declared

scholarly journals Activation of hypoxia-inducible factor 1 in human T-cell leukaemia virus type 1-infected cell lines and primary adult T-cell leukaemia cells

2007 ◽  
Vol 406 (2) ◽  
pp. 317-323 ◽  
Author(s):  
Mariko Tomita ◽  
Gregg L. Semenza ◽  
Canine Michiels ◽  
Takehiro Matsuda ◽  
Jun-Nosuke Uchihara ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protein Expression ◽  
Cell Lines ◽  
Transcriptional Activity ◽  
Cell Leukaemia ◽  
Leukaemia Virus ◽  
Human T Cell ◽  
T Cell Lines

HTLV-1 (human T-cell leukaemia virus type 1) is the causative agent for ATL (adult T-cell leukaemia). HTLV-1 Tax can activate the PI3K (phosphoinositide 3-kinase)/Akt signalling pathway, which is responsible for survival of HTLV-1-infected T-cells. HIFs (hypoxia-inducible factors) are transcriptional regulators that play a central role in the response to hypoxia. Overexpression of HIF-1α in many cancers is associated with a poor response to treatment and increased patient mortality. Our objectives in the present study were to investigate whether HIF-1 was activated in HTLV-1-infected T-cells and to elucidate the molecular mechanisms of HIF-1 activation by focusing on the PI3K/Akt signalling pathway. We detected a potent pathway that activated HIF-1 in the HTLV-1-infected T-cells under a normal oxygen concentration. Enhanced HIF-1α protein expression and HIF-1 DNA-binding activity were exhibited in HTLV-1-infected T-cell lines. Knockdown of HIF-1α by siRNA (small interfering RNA) suppressed the growth and VEGF (vascular endothelial growth factor) expression of the HTLV-1-infected T-cell line. HIF-1 protein accumulation and transcriptional activity were enhanced by Tax, which was inhibited by dominant-negative Akt. Importantly, mutant forms of Tax that are defective in activation of the PI3K/Akt pathway failed to induce HIF-1 transcriptional activity. The PI3K inhibitor LY294002 suppressed HIF-1α protein expression, HIF-1 DNA-binding and HIF-1 transcriptional activity in HTLV-1-infected T-cell lines. In primary ATL cells, HIF-1α protein levels were strongly correlated with levels of phosphorylated Akt. The results of the present study suggest that PI3K/Akt activation induced by Tax leads to activation of HIF-1. As HIF-1 plays a major role in tumour progression, it may represent a molecular target for the development of novel ATL therapeutics.

scholarly journals Tax protein of human T-cell leukaemia virus type 1 induces interleukin 17 gene expression in T cells

2004 ◽  
Vol 85 (7) ◽  
pp. 1921-1932 ◽  
Author(s):  
Madeleine Duc Dodon ◽  
Zhenlin Li ◽  
Samir Hamaia ◽  
Louis Gazzolo
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Type ◽  
Transcriptional Activation ◽  
Cell Leukaemia ◽  
Interleukin 17 ◽  
Leukaemia Virus ◽  
Tax Protein ◽  
Human T Cell

Tax protein of human T-cell leukaemia virus type 1 (HTLV-1) induces the expression of several cellular genes that are involved in T cell activation and proliferation. In this study, it was observed that Tax upregulated the expression of human interleukin 17 (IL17), a cytokine mainly produced by activated CD4+ memory T cells. Indeed, IL17 mRNA was highly expressed in HTLV-1-infected T cells as well as in Tax-expressing Jurkat T cells, whereas it was not detectable in HTLV-1-negative T cell lines. The clinical relevance of these observations was further demonstrated by quantitative assessment of IL17 expression in lymphocytes isolated from one HTLV-1-infected patient. To define the transcriptional activation of the IL17 gene by Tax, the 5′-flanking region of this gene was cloned and a reporter gene analysis performed. The presence of a Tax-responsive region spanning 614 bp upstream of the initiation start site was identified, in HeLa as well as in Jurkat cells, stimulated with phorbol myristate acetate and Ca2+ ionophore. Finally, Tax mutants were used to show that the transcriptional activation of the IL17 promoter by Tax was dependent on the CREB/ATF pathway. As IL17 upregulates the expression of several pro-inflammatory cytokines, these observations provide new insights into the involvement of the Tax protein in the pathophysiology of HTLV-1-associated inflammatory disorders.

scholarly journals Quantification of T cell clonality in human T cell leukaemia virus type-1 carriers can detect the development of adult T cell leukaemia early

2021 ◽  
Vol 11 (3) ◽  
Author(s):  
Sonia N. Wolf ◽  
Jana Haddow ◽  
Claire Greiller ◽  
Graham P. Taylor ◽  
Lucy B. M. Cook ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Type ◽  
Mononuclear Cells ◽  
Cell Leukaemia ◽  
Leukaemia Virus ◽  
Human T Cell ◽  
Increased Risk

AbstractAdult T cell leukaemia/lymphoma (ATL) arises from clonally expanded T cells that are infected with human T cell leukaemia virus type-1 (HTLV-1). Here, we show that ATL can be detected early in HTLV-1-carriers through quantification of T-cell receptor (TCR)Vβ subunit diversity on T-cells infected with HTLV-1 (CD3+ CCR4+ CD26− T-cells) using an ‘oligoclonality index’ (OCI-flow). We established a reference range for OCI-flow by analysing peripheral blood mononuclear cells (PBMCs) from HTLV-1-carriers who had not developed ATL in a median of 10.5 years follow up (n = 38) and patients with ATL (n = 30). In the third cohort of HTLV-1-carriers with no history or clinical evidence of ATL (n = 106), 19% of high proviral load (PVL, ≥4 copies of HTLV-1/100 PBMCs) carriers had an OCI-flow in the ATL range, >0.770. Carriers with an OCI-flow >0.770 (n = 14) had higher lymphocyte counts and PVLs and were more likely to have a family history of ATL than carriers with OCI-flow ≤0.770. ATL subsequently developed in two of these 14 carriers but no carriers with OCI-flow ≤0.770 (p = 0.03, cumulative follow-up 129 person-years). This method can be used to identify a subset of high-PVL HTLV-1-carriers at increased risk of developing ATL who may benefit from intervention therapy, prior to the detection of disease.

scholarly journals Calcium-mediated inhibition of phorbol ester and Tax trans-activation of the human T cell leukaemia virus type 1

1994 ◽  
Vol 75 (7) ◽  
pp. 1623-1631 ◽  
Author(s):  
K. F. T. Copeland ◽  
A. G. M. Haaksma ◽  
J. Goudsmit ◽  
J. L. Heeney
Keyword(s):  
T Cell ◽  
Virus Type ◽  
Phorbol Ester ◽  
Cell Leukaemia ◽  
Leukaemia Virus ◽  
Human T Cell

Protective effect of interferon ? on human T cell leukaemia virus type I infection of CD4+ T cells isolated from human cord blood

1993 ◽  
Vol 37 (2) ◽  
pp. 97-104 ◽  
Author(s):  
Beatrice Macchi ◽  
Isabella Faraoni ◽  
Antonio Mastino ◽  
Chiara D'Onofrio ◽  
Gianna Romeo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protective Effect ◽  
Cord Blood ◽  
Virus Type ◽  
Cell Leukaemia ◽  
Type I ◽  
Human Cord Blood ◽  
Leukaemia Virus ◽  
Human T Cell

scholarly journals Human T-cell leukaemia virus type 1: parasitism and pathogenesis

2017 ◽  
Vol 372 (1732) ◽  
pp. 20160272 ◽  
Author(s):  
Charles R. M. Bangham ◽  
Masao Matsuoka
Keyword(s):  
T Cell ◽  
Virus Type ◽  
Inflammatory Diseases ◽  
Spastic Paraparesis ◽  
Cell Leukaemia ◽  
Cell Contact ◽  
Leukaemia Virus ◽  
Human T Cell ◽  
Infected Cells

Human T-cell leukaemia virus type 1 (HTLV-1) causes not only adult T-cell leukaemia-lymphoma (ATL), but also inflammatory diseases including HTLV-1-associated myelopathy/tropical spastic paraparesis. HTLV-1 transmits primarily through cell-to-cell contact, and generates abundant infected cells in the host in order to survive and transmit to a new host. The resulting high proviral load is closely associated with the development of ATL and inflammatory diseases. To increase the number of infected cells, HTLV-1 changes the immunophenotype of infected cells, induces proliferation and inhibits apoptosis through the cooperative actions of two viral genes, tax and HTLV-1 bZIP factor ( HBZ ). As a result, infected cells survive, proliferate and infiltrate into the tissues, which is critical for transmission of the virus. Thus, the strategy of this virus is indivisibly linked with its pathogenesis, providing a clue for prevention and treatment of HTLV-1-induced diseases. This article is part of the themed issue ‘Human oncogenic viruses’.

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