title: Effect of ribavirin on the frequency of RNase L cleavage sites within the hepatitis C viral genome.
abstract: The mechanisms of synergy in antiviral activity of interferon-alpha and ribavirin in treating chronic hepatitis C virus (HCV) infection are still unknown. Interferon-alpha indirectly induces cleavage of viral RNA by RNase L at UU/UA dinucleotides. There is evidence that HCV genomes with a higher number of UU/UA dinucleotides are more sensitive to interferon-alpha. As a guanosine analogue, ribavirin exerts a mutagenic effect promoting G-to-A and C-to-U transitions. This study investigates whether ribavirin-induced mutagenesis causes a higher frequency of UU/UA dinucleotides in the viral progeny sequences. Increased mutational frequencies in favour of G-to-A and C-to-U transitions during ribavirin treatment was reported by Hofmann et al. (Gastroenterology 2007;132:921-930). Overall, 937 nucleotide sequences from that publication were reanalysed for RNase L cleavage sites. These included HCV NS3 quasispecies from three patients with ribavirin monotherapy and NS5B quasispecies from patients who received ribavirin alone (n = 7) or in combination with interferon-alpha (n = 7) at baseline and during treatment; NS5B quasispecies from a subgenomic HCV replicon system after 24, 48 and 72 h of cultivation with or without ribavirin or with levovirin. For NS3 quasispecies during ribavirin monotherapy and NS5B quasispecies from patients who received ribavirin alone or in combination with interferon-alpha, analysis of RNase L cleavage sites did not reveal changes during treatment or differences between treatment regimes. Similarly, RNaseL cleavage sites from NS5B quasispecies of the HCV replicon did not differ significantly between time points or treatments. In conclusion, Ribavirin-induced mutagenesis did not increase RNase L cleavage sites (UU/UA dinucleotides) within the HCV NS3 or NS5B encoding regions.
authors.affiliation: Medizinische Klinik I, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt/Main, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Mihm
authors.forename: W P
authors.initials: WP
authors.lastname: Hofmann
authors.forename: C
authors.initials: C
authors.lastname: Welsch
authors.forename: A
authors.initials: A
authors.lastname: Polta
authors.forename: T
authors.initials: T
authors.lastname: Lengauer
authors.forename: S
authors.initials: S
authors.lastname: Zeuzem
authors.forename: C
authors.initials: C
authors.lastname: Sarrazin
authors.forename: E
authors.initials: E
authors.lastname: Herrmann
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001665:Binding Sites; D002460:Cell Line; D004722:Endoribonucleases / Q000378:metabolism*; D016679:Genome, Viral; D016174:Hepacivirus / Q000187:drug effects*; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D017354:Point Mutation; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011994:Recombinant Proteins; D012254:Ribavirin / Q000494:pharmacology / Q000627:therapeutic use*; D012641:Selection, Genetic; D017361:Viral Nonstructural Proteins / Q000235:genetics; D014776:Virus Cultivation; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D004722:Endoribonucleases; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C031956:2-5A-dependent ribonuclease; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a