Stromal Cell-Mediated Suppression of Human T-Cell Leukemia Virus Type 1 Expression In Vitro and In Vivo by Type I Interferon

Kinpara, Shuichi; Hasegawa, Atsuhiko; Utsunomiya, Atae; Nishitsuji, Hironori; Furukawa, Hiroyuki; Masuda, Tohru; Kannagi, Mari

doi:10.1128/jvi.02564-08

Cited by 50 publications

(63 citation statements)

References 36 publications

(36 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Surprisingly, neither treatment of immature DCs with recombinant IFN-α nor culture with supernatant from mature DCs (that contains high amounts of physiological type I IFNs) was able to restrict HTLV-1 infection. This is in contrast with previous studies [19,20] and suggests that therapeutic failure of type I IFN therapy used in some ATL chemotherapy protocols [21] could be due to resistance of DCs to IFN-α treatment. This hypothesis would need confirmation through clinical trials monitoring the proviral load in DCs from ATL patients throughout anti-viral therapy.…”

contrasting

confidence: 54%

“…This led to the observation that the strength of HTLV-1 restriction correlates the level of DC maturation. Because mature DCs produce high amounts of IFN-α and because it is well established that IFN-α has anti-HTLV-1 activity in other cell types [19,20], we then asked whether HTLV-1 restriction in mature DCs was due to the antiviral effect of IFN-α. Surprisingly, neither treatment of immature DCs with recombinant IFN-α nor culture with supernatant from mature DCs (that contains high amounts of physiological type I IFNs) was able to restrict HTLV-1 infection.…”

mentioning

confidence: 99%

See 1 more Smart Citation

How Does Susceptibility to HTLV-1 Infection Varies With the Maturation State of Dendritic Cells?

et al. 2017

View full text Add to dashboard Cite

Keywords: dendritic cells • dendritic cell maturation • HTLV-1 infection • viral infectionHuman T-lymphotropic virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy. In patients, the provirus is detected in CD4 + T cells. HTLV-1 also infects blood or monocyte-derived dendritic cells (DCs) in vitro. Since DCs are more susceptible to HTLV-1 infection than autologous T cells, it has been suggested that they might be intermediaries for the viral spread to lymphocytes. DCs can switch from an immature to a mature state after contact with pathogens. In other viral infection, mature DCs are more efficient than immature DCs in viral transmission to T cells. In this editorial, we highlight a work demonstrating that mature DCs are unable to transmit HTLV-1 to T cells and discuss the mechanism of such restriction.HTLV-1 was identified as the first human oncogenic retrovirus [1,2]. It is the etiological agent of adult T-cell leukemia (ATL), an oligoclonal malignancy of infected CD4 + T lymphocytes, and of tropical spastic paraparesis, a chronic progressive inflammatory disease. Five to ten million individuals are HTLV-1 carriers worldwide [3], a probably underestimated number. HTLV-1 inter-individual transmission relies on mother-to-child transmission through prolonged breastfeeding, on sexual transmission and on transmission with contaminated blood products [4].In chronically infected individuals, HTLV-1 proviral DNA is mainly found in CD4 + T cells, but several reports have demonstrated that others immune cell types are infected by HTLV-1 in vivo [5][6][7]. These cell types include DCs, which are specialized antigen-presenting cells and essential mediators in shaping innate and adaptive immunity [8]. In vitro studies conducted by our lab and others confirmed that HTLV-1 productively infects myeloid blood DCs [7] and monocyte-derived DCs (MDDCs) [9][10][11]. Of note, exposure of target cells to cell-free viruses only leads to very low levels of productive infection [9], consistent with the observation that efficient infection of target cells requires close cell-to-cell contacts with infected donor cells [12]. Viral entry in T cells requires expression of the HTLV-1 receptor complex, in other words, neuropilin-1 and heparan sulfate proteoglycans, used for binding [13], and the glucose transporter Glut-1, required for fusion [14], while viral binding to DCs was also shown to require DC-SIGN [11].Importantly, we demonstrated that primary MDDCs are more susceptible to productive HTLV-1 infection than their autologous T cells [9]. Given that productively infected MDDCs are able to transfer HTLV-1 to T cells [7,9,11], it is thus proposed that DCs might be important intermediaries for HTLV-1 spread to T cells in newly infected individuals.Upon stimulation, DCs can switch from an immature to a mature state characterized by morphological, phenotypic and functional changes [15]. Interestingly, in the context of HIV-1, another retrovirus that spreads from DCs to T cells in ne...

show abstract

contrasting

confidence: 54%

mentioning

confidence: 99%

How Does Susceptibility to HTLV-1 Infection Varies With the Maturation State of Dendritic Cells?

et al. 2017

View full text Add to dashboard Cite

show abstract

“…It was shown that HTLV-1 gag mRNA decreased when HTLV-1-immortalized (interleukin 2 [IL-2]-dependent) T cells were cocultured with human 293T or murine NIH 3T3 nonlymphoid stromal cells (30). This effect was abolished when a poly-clonal neutralizing antibody against IFN-␤ (but not against IFN-␣) was added, indicating that IFN-␤ produced by stromal cells could inhibit virus production.…”

mentioning

confidence: 93%

Alpha Interferon Restricts Human T-Lymphotropic Virus Type 1 and 2 De Novo Infection through PKR Activation

Cachat

Chevalier

Alais

et al. 2013

J Virol

View full text Add to dashboard Cite

“…HUT102 cell line, which has the capacity for IL-2-independent cell growth, was also used (1). ILT-Hod and HUT102 were kind gifts from Dr. Mari Kannagi (Tokyo Medical and Dental University, Tokyo, Japan) and Dr. Masahiro Fujii (Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan) in 2008, who published the manuscripts using these cell lines (18,19). Cell identities were not authenticated by the authors other than confirming the cell lines are ATL cells by Southern blot analysis for viral gene integration and status of Tax expression in addition to characteristic T-cell phenotypic markers.…”

Section: Cellsmentioning

confidence: 99%

JAK–STAT and JAK–PI3K–mTORC1 Pathways Regulate Telomerase Transcriptionally and Posttranslationally in ATL Cells

Yamada

Ozaki

Akiyama

et al. 2012

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Adult T-cell leukemia (ATL) is a heterogeneous tumor that is resistant to chemotherapy. Telomerase activity plays a critical role in tumorigenesis and is associated with the prognosis of ATL patients. Interleukin (IL)-2 commonly promotes tumor growth in chronic ATL cells. The signaling pathways involved in IL-2-regulated telomerase activation were studied in ATL cells derived from chronic ATL patients. IL-2 challenge enhanced tyrosine phosphorylation of Janus-activated kinase (JAK)1-3 and STAT5, and induced JAK1 and JAK2 to associate with STAT5 in IL-2-dependent ATL cells. Chromatin immunoprecipitation assays revealed that STAT5 directly bound to the human telomerase reverse transcriptase (hTERT) promoter. STAT5 short interfering RNA inhibited hTERT transcription in IL-2-stimulated ATL cells. Inhibitors of PI3K, HSP90, and mTOR reduced IL-2-induced hTERT mRNA, protein expression, and telomerase activity. AKT, HSP90, mTOR, S6 kinase, and hTERT immunoprecipitate from IL-2-stimulated cells contained telomerase activity, suggesting that hTERT directly interacts with, and is regulated by, these proteins. Binding of the p85 regulatory subunit of PI3K to JAK2 was enhanced in an IL-2-dependent manner, indicating that JAK2 propagates activation signals from the IL-2 receptor and links hTERT activation to both the STAT5 and PI3K pathways. Finally, IL-2-induced activation of telomerase and STAT5 was observed in primary leukemic cells. These results indicate that IL-2 stimulation induces hTERT activation through the JAK/STAT pathway and the JAK/PI3K/AKT/HSP90/ mTORC1 pathway in IL-2-responsive ATL cells. These signaling proteins represent novel and promising molecular therapeutic targets for IL-2-dependent ATL.

show abstract

Stromal Cell-Mediated Suppression of Human T-Cell Leukemia Virus Type 1 Expression In Vitro and In Vivo by Type I Interferon

Abstract: Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL),

Cited by 50 publications

References 36 publications

How Does Susceptibility to HTLV-1 Infection Varies With the Maturation State of Dendritic Cells?

How Does Susceptibility to HTLV-1 Infection Varies With the Maturation State of Dendritic Cells?

Alpha Interferon Restricts Human T-Lymphotropic Virus Type 1 and 2 De Novo Infection through PKR Activation

JAK–STAT and JAK–PI3K–mTORC1 Pathways Regulate Telomerase Transcriptionally and Posttranslationally in ATL Cells

Contact Info

Product

Resources

About