Ribavirin Up‐Regulates the Activity of Double‐Stranded RNA‐Activated Protein Kinase and Enhances the Action of Interferon‐α against Hepatitis C Virus

Liu, Wei Liang; Su, Wen; Cheng, Ching Wei; Hwang, Lih Hwa; Wang, Chih Chiang; Chen, Huiling; Chen, Ding‐Shinn; Lai, Ming Yang

doi:10.1086/518894

Cited by 34 publications

(33 citation statements)

References 48 publications

(37 reference statements)

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“…The antiviral function of IFN-␣ depends on direct antiviral actions through transcriptional activation of many ISGs. Two ISGs, encoding OAS and PKR, have been shown to inhibit HCV infection in several studies (26,41,63,66,69,71), and we confirmed their anti-HCV function as described above. We then studied the impact of the Ras/Raf/MEK pathway on these two ISGs.…”

Section: Knockdown Of Raf1 Inhibits Hcv Replicationsupporting

confidence: 87%

Activation of the Ras/Raf/MEK Pathway Facilitates Hepatitis C Virus Replication via Attenuation of the Interferon-JAK-STAT Pathway

Zhang

Gong

et al. 2012

J Virol

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Hepatitis C virus (HCV) is a major cause of chronic liver diseases worldwide, often leading to the development of hepatocellular carcinoma (HCC). Constitutive activation of the Ras/Raf/MEK pathway is responsible for approximately 30% of cancers. Here we attempted to address the correlation between activation of this pathway and HCV replication. We showed that knockdown of Raf1 inhibits HCV replication, while activation of the Ras/Raf/MEK pathway by V12, a constitutively active form of Ras, stimulates HCV replication. We further demonstrated that this effect is regulated through attenuation of the interferon (IFN)-JAK-STAT pathway. Activation of the Ras/Raf/MEK pathway downregulates the expression of IFN-stimulated genes (ISGs), attenuates the phosphorylation of STAT1/2, and inhibits the expression of interferon (alpha, beta, and omega) receptors 1 and 2 (IFNAR1/2). Furthermore, we observed that HCV infection activates the Ras/Raf/MEK pathway. Thus, we propose that during HCV infection, the Ras/Raf/MEK pathway is activated, which in turn attenuates the IFN-JAK-STAT pathway, resulting in stimulation of HCV replication.

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Section: Knockdown Of Raf1 Inhibits Hcv Replicationsupporting

confidence: 87%

Activation of the Ras/Raf/MEK Pathway Facilitates Hepatitis C Virus Replication via Attenuation of the Interferon-JAK-STAT Pathway

Zhang

Gong

et al. 2012

J Virol

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“…6). A previous study reported that reduced eukaryotic initiation factor 2 alpha subunit (eIF2α) phosphorylation was associated with increase in HCV protein synthetic rates and viral RNA replication (32). In addition, DAPK was reported to regulate eIF2-α (33).…”

Section: The Mtor-independent Pathways Might Be Involved In the Antivmentioning

confidence: 99%

Pegylated IFN-α suppresses hepatitis C virus by promoting the DAPK-mTOR pathway

Liu

Yang

Hsu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Death-associated protein kinase (DAPK) has been found to be induced by IFN, but its antiviral activity remains elusive. Therefore, we investigated whether DAPK plays a role in the pegylated IFN-α (peg-IFN-α)-induced antiviral activity against hepatitis C virus (HCV) replication. Primary human hepatocytes, Huh-7, and infectious HCV cell culture were used to study the relationship between peg-IFN-α and the DAPK-mammalian target of rapamycin (mTOR) pathways. The activation of DAPK and signaling pathways were determined using immunoblotting. By silencing DAPK and mTOR, we further assessed the role of DAPK and mTOR in the peg-IFN-α-induced suppression of HCV replication. Peg-IFN-α up-regulated the expression of DAPK and mTOR, which was associated with the suppression of HCV replication. Overexpression of DAPK enhanced mTOR expression and then inhibited HCV replication. In addition, knockdown of DAPK reduced the expression of mTOR in peg-IFN-α-treated cells, whereas silencing of mTOR had no effect on DAPK expression, suggesting mTOR may be a downstream effector of DAPK. More importantly, knockdown of DAPK or mTOR significantly mitigated the inhibitory effects of peg-IFN-α on HCV replication. In conclusion, our data suggest that the DAPK-mTOR pathway is critical for anti-HCV effects of peg-IFN-α.H epatitis C virus (HCV) infection is a major health problem worldwide that may lead to chronic hepatitis, liver cirrhosis, hepatocellular carcinoma, and liver failure (1). Although the development of direct antiviral agents (DAAs), such as HCV protease and polymerase inhibitors, has revolutionized the treatment of HCV infection (2, 3), considering the high cost of IFN-free DAAs, combination therapy with pegylated IFN-α (peg-IFN-α) and ribavirin (RBV) may remain for a while, especially in countries with limited medical resources (4-6). However, many HCV patients fail combination therapy of peg-IFN-α and RBV, and determinants of the responsiveness to IFN have not been fully understood. Therefore, it is scientifically important to identify biomarkers or mechanisms for prediction of the IFN response in patients with hepatitis C.Type I IFNs are a family of pleiotropic cytokines with known antiviral, antiproliferative, and immunomodulatory functions exerted on a wide range of cell types. IFNs bind to its receptor and lead to activation of the Janus kinase-signal transducer and activator of transcription (STAT) pathway, resulting in the association of phosphorylated STATs with IFN regulatory factor-9 to form a transcriptional activator complex, which subsequently translocates to the nucleus and activates an array of IFN-stimulated genes, such as dsRNA-dependent protein kinase (PKR), 2′,5′-oligoadenylatesynthesase, p56, and myxovirus resistance protein A (MxA) (7). Through the action of these IFN-induced genes, IFN-α confers an antiviral state on hepatocytes and exerts its anti-HCV activity in patients with chronic hepatitis C. However, the full function of the IFN-induced genes in suppression of HCV replication has not yet been compr...

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“…Although ribavirin on its own exerts a modest antiviral activity (9), its important role in HCV RNA decline and its capability to reduce the emergence of drug resistance suggest a distinct mechanism of action. Thus, the major role of ribavirin in HCV therapy may be immunomodulatory [e.g., by altering the Th1/Th2 ratio toward a more antiviral Th1-dominated immune response (10)(11)(12) and enhancing the IFNinduced gene expression (13)(14)(15)(16)]. …”

mentioning

confidence: 99%

Cleavage of the T Cell Protein Tyrosine Phosphatase by the Hepatitis C Virus Nonstructural 3/4A Protease Induces a Th1 to Th2 Shift Reversible by Ribavirin Therapy

Brenndörfer

Brass

Karthe

et al. 2014

The Journal of Immunology

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Ribavirin has proven to be a key component of hepatitis C therapies both involving IFNs and new direct-acting antivirals. The hepatitis C virus–mediated interference with intrahepatic immunity by cleavage of mitochondrial antiviral signaling protein (MAVS) and T cell protein tyrosine phosphatase (TCPTP) suggests an avenue for compounds that may counteract these effects. We therefore studied the effects of ribavirin, with or without inhibition of the nonstructural (NS)3/4A protease, on intrahepatic immunity. The intrahepatic immunity of wild-type and NS3/4A-transgenic mice was determined by Western blot, ELISA, flow cytometry, and survival analysis. Various MAVS or TCPTP constructs were injected hydrodynamically to study their relevance. Ribavirin pretreatment was performed in mice expressing a functional or inhibited NS3/4A protease to analyze its effect on NS3/4A-mediated changes. Intrahepatic NS3/4A expression made mice resistant to TNF-α–induced liver damage and caused an alteration of the intrahepatic cytokine (IFN-γ and IL-10) and chemokine (CCL3, CCL17, CCL22, CXCL9, and CXCL11) profiles toward an anti-inflammatory state. Consistent with this, the number of intrahepatic Th1 cells and IFN-γ+ T cells in NS3/4A-transgenic mice decreased, whereas the amount of Th2 cells increased. These effects could be reversed by injection of uncleavable TCPTP but not uncleavable MAVS and were absent in a mouse expressing a nonfunctional NS3/4A protease. Importantly, the NS3/4A-mediated effects were reversed by ribavirin treatment. Thus, cleavage of TCPTP by NS3/4A induces a shift of the intrahepatic immune response toward a nonantiviral Th2-dominated immunity. These effects are reversed by ribavirin, supporting that ribavirin complements the effects of direct-acting antivirals as an immunomodulatory compound.

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Ribavirin Up‐Regulates the Activity of Double‐Stranded RNA‐Activated Protein Kinase and Enhances the Action of Interferon‐α against Hepatitis C Virus

Cited by 34 publications

References 48 publications

Activation of the Ras/Raf/MEK Pathway Facilitates Hepatitis C Virus Replication via Attenuation of the Interferon-JAK-STAT Pathway

Activation of the Ras/Raf/MEK Pathway Facilitates Hepatitis C Virus Replication via Attenuation of the Interferon-JAK-STAT Pathway

Pegylated IFN-α suppresses hepatitis C virus by promoting the DAPK-mTOR pathway

Cleavage of the T Cell Protein Tyrosine Phosphatase by the Hepatitis C Virus Nonstructural 3/4A Protease Induces a Th1 to Th2 Shift Reversible by Ribavirin Therapy

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