Ribavirin Enhances IFN-α Signalling and MxA Expression: A Novel Immune Modulation Mechanism during Treatment of HCV

Stevenson, Nigel J.; Murphy, Alison G.; Bourke, Nollaig M.; Keogh, Catherine; Hegarty, John E.; O’Farrelly, Cliona

doi:10.1371/journal.pone.0027866

Cited by 46 publications

(40 citation statements)

References 28 publications

(21 reference statements)

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“…The recent observations made by Rotman et al ,24 who failed to find a generalised RBV-triggered ISG activation in vivo , conflict with the RBV-mediated activation of ISGs reported by others in hepatic and non-hepatic transformed cell lines 21 31 32. The mechanisms underlying ISG activation remain controversial and the ability of RBV to enhance signal transducer and activator of transcriptions (STATs) phosphorylation and interferon sensitive response element (ISRE)-dependent transcription has been strongly challenged 22.…”

Section: Resultsmentioning

confidence: 77%

Ribavirin restores IFNα responsiveness in HCV-infected livers by epigenetic remodelling at interferon stimulated genes

Testoni

Durantel

Lebossé

et al. 2015

Gut

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Section: Resultsmentioning

confidence: 77%

Ribavirin restores IFNα responsiveness in HCV-infected livers by epigenetic remodelling at interferon stimulated genes

Testoni

Durantel

Lebossé

et al. 2015

Gut

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“…Th1 lymphocytes secrete IFN-gamma and Il -2 among other cytokines (16). Ribavirin enhances the specific interferon sensitive gene (ISG) expression by amplifying the IFN-a-JAK/STAT pathway and that enhances IFN-a anti-viral activity against HCV (17,18).…”

Section: Introductionmentioning

confidence: 99%

Could Inosine pranobex and Ribavirin in combination restore immune competence in chronic HCV advanced liver disease?

Nikolova¹,

Antonov²,

Mateva³

et al. 2014

MedInform

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The management of patients with advanced chronic HCV liver disease is still a problem. There is insufficient data about the role of immunomodulatory agents. The aim of the present study was to evaluate the benefit of prolonged co-administration of Inosine pranobex (Isoprinosine) and Ribavirin in patients with HCV advanced liver disease and to assess the dynamics of the IP-10 serum levels and thus -changes in the immune status of patients. Methods: Five patients (2 males, 3 females; median age 63), with chronic HCV genotype 1 infection were studied (with failed standard bitherapy). All patients received Ribavirin and Isoprinosine. HCVRNA was measured at baseline and at day 40, month 3, 6 and 12 during treatment. IP-10 levels -at baseline and at day 10, 20, 40, 60, month 3, 6 and 12. Results: IP-10 levels were elevated in all patients at the baseline. An increase at day 10 or 20 was found in 4/5 patients and reduction at day 40 or 60 in same 4 patients. At month 12 the levels were significantly reduced (P=0.043). There was also an initially slight increase of ALT and subsequent reduction (P=0.043). The count of platelets increased in 4/5 patients. No effect on viral load was found. Conclusion: The therapeutic regime is well tolerated, no severe adverse events were documented. An improvement of the disease severity and liver inflammation were observed, with no effect on the viral load. We found reduction of IP-10 levels at month 12 -a sign of immune competence restoration.

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“…For example, IFN-α produced by pDCs was necessary In this clinical trial in which patients were randomized to weight-based or low-dose RBV, treatment with low-dose RBV was not associated with an increased risk of treatment relapse in a bivariable model of treatment outcome, a conclusion limited by the small sample size of the clinical study (8). Because RBV is known to sensitize the host to the effect of IFN and reduce hepatic transaminases (17,(36)(37)(38), it is possible that the IFN signature described herein could be partially attributed to interindividual differences in responsiveness to RBV. To explore this possibility, our present findings should be assessed in future IFN-and RBVfree DAA clinical trials.…”

mentioning

confidence: 99%

Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome

Meissner¹,

Wu²,

Osinusi³

et al. 2014

J. Clin. Invest.

187

190

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BACKGROUND. Hepatitis C virus (HCV) infects approximately 170 million people worldwide and may lead to cirrhosis and hepatocellular carcinoma in chronically infected individuals. Treatment is rapidly evolving from IFN-α-based therapies to IFN-α-free regimens that consist of directly acting antiviral agents (DAAs), which demonstrate improved efficacy and tolerability in clinical trials. Virologic relapse after DAA therapy is a common cause of treatment failure; however, it is not clear why relapse occurs or whether certain individuals are more prone to recurrent viremia. METHODS.We conducted a clinical trial using the DAA sofosbuvir plus ribavirin (SOF/RBV) and performed detailed mRNA expression analysis in liver and peripheral blood from patients who achieved either a sustained virologic response (SVR) or relapsed. RESULTS.On-treatment viral clearance was accompanied by rapid downregulation of IFN-stimulated genes (ISGs) in liver and blood, regardless of treatment outcome. Analysis of paired pretreatment and end of treatment (EOT) liver biopsies from SVR patients showed that viral clearance was accompanied by decreased expression of type II and III IFNs, but unexpectedly increased expression of the type I IFN IFNA2. mRNA expression of ISGs was higher in EOT liver biopsies of patients who achieved SVR than in patients who later relapsed. CONCLUSION.These results suggest that restoration of type I intrahepatic IFN signaling by EOT may facilitate HCV eradication and prevention of relapse upon withdrawal of SOF/RBV. TRIAL REGISTRATION. ClinicalTrials.gov NCT01441180. FUNDING. Intramural Programs of the National Institute of Allergy and Infectious The Journal of Clinical Investigation C l i n i C a l M e d i C i n e3 3 5 3 jci.orgVolume 124 Number 8 August 2014We next evaluated on-treatment serum protein levels of select chemokines and cytokines and observed similar expression at baseline and during treatment comparing patients who achieved SVR versus those who relapsed (Supplemental Table 3). Serum levels of the IFN-inducible cytokine IP-10, the protein product of the CXCL10 gene that was downregulated in liver (Figure 2A), correlated significantly with baseline viral load ( Figure 3A). Expression decreased rapidly on-treatment, regardless of treatment outcome, and increased with relapse ( Figure 3B). Viral kinetic and IP-10 decline were significantly correlated ( Figure 3C and Table 1). IL-10 and IFN-γ decreased modestly during treatment, while expression of most other proteins did not change, including TGF-β1 and TIMP1, which are associated with hepatic fibrosis (Supplemental Table 3 and ref. 25).To assess whether a similar pattern of gene expression changes could be observed in the periphery, we performed microarray mRNA analysis in PBMCs collected before treatment, early in treatment (day 6-11), and at EOT (week 24) and identified a significant decrease of IFN signaling during treatment (Supplemental Figure 2 and Supplemental Table 4). qRT-PCR analysis in PBMCs confirmed rapid and sustained downregulation of I...

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Ribavirin Enhances IFN-α Signalling and MxA Expression: A Novel Immune Modulation Mechanism during Treatment of HCV

Cited by 46 publications

References 28 publications

Ribavirin restores IFNα responsiveness in HCV-infected livers by epigenetic remodelling at interferon stimulated genes

Ribavirin restores IFNα responsiveness in HCV-infected livers by epigenetic remodelling at interferon stimulated genes

Could Inosine pranobex and Ribavirin in combination restore immune competence in chronic HCV advanced liver disease?

Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome

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