Suppression of Type I Interferon Production by Human T-Cell Leukemia Virus Type 1 Oncoprotein Tax through Inhibition of IRF3 Phosphorylation

Yuen, Chun-Kit; Chan, Cadia; Fung, Sin‐Yee; Wang, Pei‐Hui; Wong, Wan-Man; Tang, Ho Man; Yuen, Kit‐San; Chan, Chi-Ping; Jin, Dong Yan; Kok, Kin‐Hang

doi:10.1128/jvi.00129-16

Cited by 30 publications

(28 citation statements)

References 66 publications

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“…Moreover, similar results were obtained by coculturing JETWT35 cells with MT-2 cells ( Fig. 4C), which is another donor cell line widely used for HTLV-1 infection (38)(39)(40)(41)(42)(43). Interestingly, this inhibition of HTLV-1 transmission by PPS became inefficient when PPS was added to the coculture 12 h later ( Fig.…”

supporting

confidence: 79%

Pentosan Polysulfate Demonstrates Anti-human T-Cell Leukemia Virus Type 1 ActivitiesIn VitroandIn Vivo

Yasunaga

Ohshima

et al. 2019

J Virol

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Human T-cell leukemia virus type 1 (HTLV-1) infection causes T-cell leukemia and inflammatory diseases, most notably including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The underlying mechanism for the pathogenesis of HAM/TSP remains unclear. According to a recent clinical trial, a humanized antibody that targets CCR4 ϩ cells ameliorates inflammation by reducing the number of infected cells in the central nervous system; this result suggests that the transmigration of HTLV-1-infected cells plays a crucial role in HAM/TSP. Partly due to the blood-brain barrier, current treatments for HAM/TSP are mostly palliative. Pentosan polysulfate (PPS), a semisynthetic glycosaminoglycan, has recently been used to treat HAM/TSP and was found to alleviate the symptoms. In this study, we investigated the effect of PPS on HTLV-1-infected cells and provide evidence for its efficacy in HAM/TSP. PPS was cytotoxic to certain HTLV-1-infected cells and significantly suppressed HTLV-1 virion production. PPS also efficiently inhibited HTLV-1 cell-cell transmission in T cells. In addition, PPS blocked HTLV-1 infection of primary endothelial cells (human umbilical vascular endothelial cells) and suppressed the subsequent induction of proinflammatory cytokine expression. Furthermore, PPS was found to inhibit the adhesion and transmigration of HTLV-1-infected cells. We also confirmed the anti-HTLV-1 effect of PPS in vivo using two mouse models. PPS blocked HTLV-1 infection in a mouse model with peripheral blood mononuclear cell (PBMC)-humanized NOD-scid IL2Rgamma null (huPBMC NSG) mice. PPS was also found to suppress the development of dermatitis and lung damage in HTLV-1 bZIP factor (HBZ)-transgenic (HBZ-Tg) mice, an HTLV-1 transgenic mouse model in which the mice develop systemic inflammation. IMPORTANCE HTLV-1 is the first human retrovirus to have been identified and is endemic in certain areas worldwide. HTLV-1 infection leads to the development of an inflammatory disease called HAM/TSP, a myelopathy characterized by slowly progressive spastic paraparesis. There have been no effective therapeutics available for HAM/TSP, but recently, a semisynthetic glycosaminoglycan, named pentosan polysulfate (PPS), has been found to alleviate the symptoms of HAM/TSP. Here we conducted a comprehensive study on the effect of PPS both in vitro and in vivo. PPS demonstrated anti-HTLV-1 potential in infected cell lines, as shown by its suppressive effects on HTLV-1 replication and transmission and on the transmigration of infected T cells. Moreover, results obtained from two HTLV-1 mouse models demonstrate that PPS inhibits HTLV-1 infection and inflammation development in vivo. Our work offers insights into the treatment of HAM/TSP by PPS and also suggests its possible use for treating other HTLV-1-induced inflammatory diseases.

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supporting

confidence: 79%

Pentosan Polysulfate Demonstrates Anti-human T-Cell Leukemia Virus Type 1 ActivitiesIn VitroandIn Vivo

Yasunaga

Ohshima

et al. 2019

J Virol

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“…Western blot analysis, coimmunoprecipitation, and quantitative RT-PCR were performed as described previously (6,43,44). For Western blot analysis, cells were lysed in RIPA buffer (10 mM Tris-Cl, pH 8.0, 1 mM EDTA, 1% Triton X-100, 0.1% sodium deoxycholate, 0.1% SDS, 140 mM NaCl, and 1 mM PMSF) that was supplemented with a protease inhibitor cocktail (BioTools, Jupiter, FL, USA).…”

Section: Protein and Rna Analysismentioning

confidence: 99%

Antiviral activity of double‐stranded RNA‐binding protein PACT against influenza A virus mediated via suppression of viral RNA polymerase

et al. 2018

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PACT is a double-stranded RNA-binding protein that has been implicated in host-influenza A virus (IAV) interaction. PACT facilitates the action of RIG-I in the activation of the type I IFN response, which is suppressed by the viral nonstructural protein NS1. PACT is also known to interact with the IAV RNA polymerase subunit PA. Exactly how PACT exerts its antiviral activity during IAV infection remains to be elucidated. In the current study, we demonstrated the interplay between PACT and IAV polymerase. Induction of IFN-β by the IAV RNP complex was most robust when both RIG-I and PACT were expressed. PACT-dependent activation of IFN-β production was suppressed by the IAV polymerase subunits, polymerase acidic protein, polymerase basic protein 1 (PB1), and PB2. PACT associated with PA, PB1, and PB2. Compromising PACT in IAV-infected A549 cells resulted in the augmentation of viral RNA (vRNA) transcription and replication and IFN-β production. Furthermore, vRNA replication was boosted by knockdown of PACT in both A549 cells and IFN-deficient Vero cells. Thus, the antiviral activity of PACT is mediated primarily via its interaction with and inhibition of IAV polymerase. Taken together, our findings reveal a new facet of the host-IAV interaction in which the interplay between PACT and IAV polymerase affects the outcome of viral infection and antiviral response.-Chan, C.-P., Yuen, C.-K., Cheung, P.-H. H., Fung, S.-Y., Lui, P.-Y., Chen, H., Kok, K.-H., Jin, D.-Y. Antiviral activity of double-stranded RNA-binding protein PACT against influenza A virus mediated via suppression of viral RNA polymerase.

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“…However, studies came to contradicting results on how that influences the production of IFNβ. While one group showed that Tax activates TBK1 and the production of IFNβ (86), another group showed that Tax suppresses the IFN production by interaction with TBK1 (87). Interestingly, when a recent study tested how the rabies virus P protein of street strains behaves compared to laboratory-adapted strains with regard to the induction of type I IFN, they found that both street strains and laboratory strains inhibit TBK1-mediated signaling, but only the P protein of street strains also interacts with and inhibits IKKε-inducible IRF3dependent IFNβ expression (88) (Figure 1).…”

Section: Activation Of Transcription Factors and Ifn Transcriptionmentioning

confidence: 99%

Viral Evasion Strategies in Type I IFN Signaling – A Summary of Recent Developments

2016

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The immune system protects the organism against infections and the damage associated with them. The first line of defense against pathogens is the innate immune response. In the case of a viral infection, it induces the interferon (IFN) signaling cascade and eventually the expression of type I IFN, which then causes an antiviral state in the cells. However, many viruses have developed strategies to counteract this mechanism and prevent the production of IFN. In order to modulate or inhibit the IFN signaling cascade in their favor, viruses have found ways to interfere at every single step of the cascade, for example, by inducing protein degradation or cleavage, or by mediate protein polyubiquitination. In this article, we will review examples of viruses that modulate the IFN response and describe the mechanisms they use.

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Suppression of Type I Interferon Production by Human T-Cell Leukemia Virus Type 1 Oncoprotein Tax through Inhibition of IRF3 Phosphorylation

Cited by 30 publications

References 66 publications

Pentosan Polysulfate Demonstrates Anti-human T-Cell Leukemia Virus Type 1 ActivitiesIn VitroandIn Vivo

Pentosan Polysulfate Demonstrates Anti-human T-Cell Leukemia Virus Type 1 ActivitiesIn VitroandIn Vivo

Antiviral activity of double‐stranded RNA‐binding protein PACT against influenza A virus mediated via suppression of viral RNA polymerase

Viral Evasion Strategies in Type I IFN Signaling – A Summary of Recent Developments

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