Mutagenic Effect of Ribavirin on Hepatitis C Nonstructural 5B Quasispecies In Vitro and During Antiviral Therapy

Hofmann, Wolf Peter; Polta, A.; Herrmann, Eva; Mihm, U.; Kronenberger, Bernd; Sonntag, Tanja; Lohmann, Volker; Schönberger, B; Zeuzem, Stefan; Sarrazin, Christoph

doi:10.1053/j.gastro.2006.12.005

Cited by 76 publications

(72 citation statements)

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“…Ribavirin is a guanosine analogue with an in vitro mutagenic effect and specifically increases the rate of C3U and G3A transitions and, to a lesser extent, U3C and A3G transitions (39). This effect has been confirmed in cell cultures for poliovirus (10,30), whereas for HCV, similar but not fully conclusive results have been obtained using primer extension assays (26) and a subgenomic replicon system (9,19,42). In other flaviviruses, ribavirininduced mutagenesis has been observed for GB virus B (22) but not for yellow fever virus (23).…”

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confidence: 87%

Effect of Ribavirin on the Mutation Rate and Spectrum of Hepatitis C Virus In Vivo

Cuevas

Gónzález-Candelas

Moya

et al. 2009

J Virol

146

130

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Their extremely error-prone replication makes RNA viruses targets for lethal mutagenesis. In the case of hepatitis C virus (HCV), the standard treatment includes ribavirin, a base analog with an in vitro mutagenic effect, but the in vivo mode of action of ribavirin remains poorly understood. Here, we test the mutagenic effects of ribavirin plus interferon treatment in vivo using a new method to estimate mutation rates based on the analysis of nonsense mutations. We apply this methodology to a large HCV sequence database containing over 15,000 reverse transcription-PCR molecular clone sequences from 74 patients infected with HCV. We obtained an estimate of the spontaneous mutation rate of ca. 10 ؊4 substitutions per site or lower, a value within the typically accepted range for RNA viruses. A roughly threefold increase in mutation rate and a significant shift in mutation spectrum were observed in samples from patients undergoing 6 months of interferon plus ribavirin treatment. This result is consistent with the known in vitro mutagenic effect of ribavirin and suggests that the antiviral effect of ribavirin plus interferon treatment is at least partly exerted through lethal mutagenesis.

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mentioning

confidence: 87%

Effect of Ribavirin on the Mutation Rate and Spectrum of Hepatitis C Virus In Vivo

Cuevas

Gónzález-Candelas

Moya

et al. 2009

J Virol

146

130

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“…Other human studies have suggested mutagenic effects for ribavirin in vivo but only at early time-points. 54,55 Mutagenic Effects (Dr. Julie Pfeiffer, University of Texas Southwestern)…”

Section: Ribavirin: Mechanism Of Action Clinical Insightsmentioning

confidence: 99%

“…In studies using HCV replication models, mutagenic effects of ribavirin have been identified by several 54,[56][57][58][59][60] but not all authors. 61 When infectivity was used as a functional readout for mutagenesis, diminished infectivity was found with ribavirin treatment of HCV cultures.58 , 60 The concentrations of ribavirin needed to achieve mutagenic effects were high (up to 400 uM) and may exceed those achieved in vivo.…”

Section: Ribavirin: Mechanism Of Action Clinical Insightsmentioning

confidence: 99%

“…61 When infectivity was used as a functional readout for mutagenesis, diminished infectivity was found with ribavirin treatment of HCV cultures.58 , 60 The concentrations of ribavirin needed to achieve mutagenic effects were high (up to 400 uM) and may exceed those achieved in vivo. These concentration differences may help to explain the discordance observed between cell culture and human studies 54,55,[62][63][64][65][66][67] (Table 3). The studies done on human samples were often limited by the circumscribed nature of the viral genomic regions sampled and the lack of a functional assay for the sequences identified.…”

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confidence: 99%

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Mechanisms of action of interferon and ribavirin in chronic hepatitis C: Summary of a workshop

et al. 2007

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The current recommended therapy for chronic hepatitis C is the combination of peginterferon and ribavirin, which results in a sustained clearance of hepatitis C virus (HCV) in at least half of patients. However, the mechanisms by which interferon alpha (IFN-α) and ribavirin act against HCV are not well defined. The importance of understanding the biological pathways, cellular effects, and antiviral activities of these agents is underscored by clinical observations that nonresponders frequently have little or no decrease in HCV RNA levels during treatment, suggesting intrinsic resistance to IFN-α. Cell culture and animal models of HCV have shown that the infection itself may block IFN-α induction and action. Still other findings suggest that individual innate and adaptive immune responses, host genetic factors, viral genetic diversity, and clinical comorbidities account for part of nonresponse to therapy. To provide an overview of the current knowledge of the mechanisms of action of IFN-α and ribavirin against HCV and offer guidance for future research, the American Association for the Study of Liver Diseases held a single topic conference entitled "Interferon and Ribavirin in Hepatitis C Virus Infection: Mechanisms of Response and Non-Response" on March [1][2][3] 2007. This article summarizes that conference. Interferons (IFNs): An OverviewThe IFNs (Dr. Howard Young, National Cancer Institute, National Institutes of Health)The type 1 IFNs [interferon alpha and beta (IFN-α/β)] comprise a family of distinct proteins1 that are produced by a wide variety of cells, including fibroblasts, epithelial cells, and hepatocytes, 2 although plasmacytoid dendritic cells (DCs) are probably the major source in most viral infections. In contrast, type II IFN [interferon gamma (IFN-γ)] is a single gene cytokine unrelated in structure to IFN-α/β that is produced largely by macrophages, natural Copyright © 2007 by the American Association for the Study of Liver Diseases.Address reprint requests to: Raymond T. Chung, M.D., Gastrointestinal Unit, GRJ724, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. rtchung@partners.org; fax: 617-643-0446.. Potential conflict of interest: Dr. Lemon is a consultant for Novartis, GlaxoSmithKline, Hoffman-LaRoche, Genelabs Technology, Abbott, Pharmasett. He also received grants from Schering-Plough and Tibotec. Dr. Chung received grants from Roche and ScheringPlough. NIH Public Access Author ManuscriptHepatology. Author manuscript; available in PMC 2009 December 29. Published in final edited form as:Hepatology. 2008 January ; 47(1): 306-320. doi:10.1002/hep.22070. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript killer (NK) cells, and T lymphocytes. Both types of IFNs interact with cells via distinct cellular receptors. The details of the signaling mechanisms by which IFN-α/β and IFN-γ induce the transcription of interferon-stimulated genes (ISGs) and depress the transcription of others are still being defined. 3 However, it is increasingly clear that the c...

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“…The region of the viral genome that codes for NS5B has been described as an important target in therapy with IFN and rBV (Kukolj et al 2005, Lu et al 2007, Lutchman et al 2007). The mechanisms that lead to viral resistance after IFN/ rBV treatment is still a matter of debate (Horiike et al 1999, Hadziyannis et al 2004, Kanda et al 2004, Hamano et al 2005, Hofmann et al 2007, Chung et al 2008, Kuntzen et al 2008, Kwong et al 2008, Nakamura et al 2008, Cannon et al 2009, Gaudieri et al 2009, rydberg et al 2009). For instance, Nelson et al (1995) showed that the mutations that occur in the HCV gene that codes for NS5B did not correlate with response to INF therapy, but Japanese studies associated IFN-rBV failure with mutations in the NS5B gene (Hamano et al 2005, Hmwe et al 2010 and Kuntzen et al (2008) showed that mutations conferred resistance to specifically targeted antiviral therapy drugs in treatmentnaïve patients infected with HCV genotype 1.…”

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confidence: 99%

Association of hepatitis C virus NS5B variants with resistance to new antiviral drugs among untreated patients

Castilho

Martins

Horbach

et al. 2011

Mem. Inst. Oswaldo Cruz

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Mutagenic Effect of Ribavirin on Hepatitis C Nonstructural 5B Quasispecies In Vitro and During Antiviral Therapy

Cited by 76 publications

References 38 publications

Effect of Ribavirin on the Mutation Rate and Spectrum of Hepatitis C Virus In Vivo

Effect of Ribavirin on the Mutation Rate and Spectrum of Hepatitis C Virus In Vivo

Mechanisms of action of interferon and ribavirin in chronic hepatitis C: Summary of a workshop

Association of hepatitis C virus NS5B variants with resistance to new antiviral drugs among untreated patients

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