Ribavirin Contributes to Hepatitis C Virus Suppression by Augmenting PDC Activation and Type 1 IFN Production

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2015 Aug 15

PMID 26274905

Citations 5

Authors

Yang Wang

David R McGivern

Liang Cheng

Guangming Li

Stanley M Lemon

Junqi Niu

Lishan Su

Natalia J Reszka-Blanco

Affiliations

Soon will be listed here.

Abstract

Ribavirin is used as a component of combination therapies for the treatment of chronic hepatitis C virus (HCV) infection together with pegylated interferon and/or direct-acting antiviral drugs. Its mechanism of action, however, is not clear. Direct antiviral activity and immunomodulatory functions have been implicated. Plasmacytoid dendritic cells (pDCs) are the principal source of type 1 interferon during viral infection. The interaction of pDCs with HCV-infected hepatocytes is the subject of intense recent investigation, but the effect of ribavirin on pDC activation has not been evaluated. In this study we showed that ribavirin augments toll-like receptors 7 and 9-mediated IFNα/β expression from pDCs and up-regulated numerous interferon-stimulated genes. Using the H77S.3 HCV infection and replication system, we showed that ribavirin enhanced the ability of activated pDCs to inhibit HCV replication, correlated with elevated induction of IFNα. Our findings provide novel evidence that ribavirin contributes to HCV inhibition by augmenting pDCs-derived type 1 IFN production.

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References

Schmittgen T, Livak K . Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008; 3(6):1101-8. DOI: 10.1038/nprot.2008.73. View

Nicot F, Legrand-Abravanel F, Lafont T, Dubois M, Saune K, Pasquier C . Serum concentrations of ribavirin and pegylated interferon and viral responses in patients infected with HIV and HCV. J Med Virol. 2008; 80(9):1523-9. DOI: 10.1002/jmv.21227. View

Lau D, Negash A, Chen J, Crochet N, Sinha M, Zhang Y . Innate immune tolerance and the role of kupffer cells in differential responses to interferon therapy among patients with HCV genotype 1 infection. Gastroenterology. 2012; 144(2):402-413.e12. PMC: 3822610. DOI: 10.1053/j.gastro.2012.10.044. View

Lawitz E, Rodriguez-Torres M, Stoehr A, Gane E, Serfaty L, Bhanja S . A phase 2B study of MK-7009 (vaniprevir) in patients with genotype 1 HCV infection who have failed previous pegylated interferon and ribavirin treatment. J Hepatol. 2013; 59(1):11-7. DOI: 10.1016/j.jhep.2013.02.008. View

Lawitz E, Sulkowski M, Jacobson I, Kraft W, Maliakkal B, Al-Ibrahim M . Characterization of vaniprevir, a hepatitis C virus NS3/4A protease inhibitor, in patients with HCV genotype 1 infection: safety, antiviral activity, resistance, and pharmacokinetics. Antiviral Res. 2013; 99(3):214-20. DOI: 10.1016/j.antiviral.2013.05.015. View

Rotman Y, Noureddin M, Feld J, Guedj J, Witthaus M, Han H . Effect of ribavirin on viral kinetics and liver gene expression in chronic hepatitis C. Gut. 2013; 63(1):161-9. PMC: 3778097. DOI: 10.1136/gutjnl-2012-303852. View

Ferreiros N, Labocha S, El-Duweik J, Schlecker C, Lotsch J, Geisslinger G . Quantitation of ribavirin in human plasma and red blood cells using LC-MS/MS. J Sep Sci. 2013; 37(5):476-83. DOI: 10.1002/jssc.201301173. View

Maynard M, Pradat P, Gagnieu M, Souvignet C, Trepo C . Prediction of sustained virological response by ribavirin plasma concentration at week 4 of therapy in hepatitis C virus genotype 1 patients. Antivir Ther. 2008; 13(4):607-11. View

Toyoda H, Kumada T, Kiriyama S, Sone Y, Tanikawa M, Hisanaga Y . Correlation of serum ribavirin concentration with pretreatment renal function estimates in patients with chronic hepatitis C receiving combination antiviral therapy with peginterferon and ribavirin. J Viral Hepat. 2008; 15(9):651-8. DOI: 10.1111/j.1365-2893.2008.01004.x. View

10.

Ibarra K, Pfeiffer J . Reduced ribavirin antiviral efficacy via nucleoside transporter-mediated drug resistance. J Virol. 2009; 83(9):4538-47. PMC: 2668478. DOI: 10.1128/JVI.02280-08. View

11.

Hezode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T . Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med. 2009; 360(18):1839-50. DOI: 10.1056/NEJMoa0807650. View

12.

Shiffman M, Morishima C, Dienstag J, Lindsay K, Hoefs J, Lee W . Effect of HCV RNA suppression during peginterferon alfa-2a maintenance therapy on clinical outcomes in the HALT-C trial. Gastroenterology. 2009; 137(6):1986-94. PMC: 3774149. DOI: 10.1053/j.gastro.2009.08.067. View

13.

Jain M, Zoellner C . Role of ribavirin in HCV treatment response: now and in the future. Expert Opin Pharmacother. 2010; 11(4):673-83. DOI: 10.1517/14656560903580001. View

14.

Takahashi K, Asabe S, Wieland S, Garaigorta U, Gastaminza P, Isogawa M . Plasmacytoid dendritic cells sense hepatitis C virus-infected cells, produce interferon, and inhibit infection. Proc Natl Acad Sci U S A. 2010; 107(16):7431-6. PMC: 2867703. DOI: 10.1073/pnas.1002301107. View

15.

Baiocchi L, De Leonardis F, Delle Monache M, Nosotti L, Conti R, Lenci I . Plasma/erythrocyte ribavirin x100 ratio as an indicator of sustained virological response in HCV genotype 1 patients with early virological response. Antivir Ther. 2010; 15(4):633-9. DOI: 10.3851/IMP1560. View

16.

Feld J, Lutchman G, Heller T, Hara K, Pfeiffer J, Leff R . Ribavirin improves early responses to peginterferon through improved interferon signaling. Gastroenterology. 2010; 139(1):154-62.e4. PMC: 2902566. DOI: 10.1053/j.gastro.2010.03.037. View

17.

Singh R, Gaiha G, Werner L, McKim K, Mlisana K, Luban J . Association of TRIM22 with the type 1 interferon response and viral control during primary HIV-1 infection. J Virol. 2010; 85(1):208-16. PMC: 3014203. DOI: 10.1128/JVI.01810-10. View

18.

Thomas E, Feld J, Li Q, Hu Z, Fried M, Liang T . Ribavirin potentiates interferon action by augmenting interferon-stimulated gene induction in hepatitis C virus cell culture models. Hepatology. 2011; 53(1):32-41. PMC: 3498496. DOI: 10.1002/hep.23985. View

19.

Shimakami T, Welsch C, Yamane D, McGivern D, Yi M, Zeuzem S . Protease inhibitor-resistant hepatitis C virus mutants with reduced fitness from impaired production of infectious virus. Gastroenterology. 2010; 140(2):667-75. PMC: 3155954. DOI: 10.1053/j.gastro.2010.10.056. View

20.

Meissner E, Wu D, Osinusi A, Bon D, Virtaneva K, Sturdevant D . Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome. J Clin Invest. 2014; 124(8):3352-63. PMC: 4109554. DOI: 10.1172/JCI75938. View