Deep sequencing reveals mutagenic effects of ribavirin during monotherapy of hepatitis C virus genotype 1-infected patients
| Autor: | Sven-Eric Schelhorn, Thomas Lengauer, Christoph Sarrazin, Thomas Berg, Stefan Zeuzem, Eva Herrmann, Simone Susser, Martin Daumer, Ulrike Mihm, Daniel Fitting, Julia Dietz, C. Füller, Gerlinde Teuber, Martin-Walter Welker, Heiner Wedemeyer |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Male
Genotype Hepatitis C virus Hepacivirus viruses Immunology Molecular Sequence Data medicine.disease_cause Microbiology Antiviral Agents Virus Deep sequencing chemistry.chemical_compound Virology Ribavirin Vaccines and Antiviral Agents medicine Humans Prospective Studies Transition (genetics) biology Base Sequence virus diseases High-Throughput Nucleotide Sequencing Hepatitis C Hepatitis C Chronic medicine.disease biology.organism_classification digestive system diseases chemistry Insect Science Mutation Female |
| Zdroj: | Journal of virology. 87(11) |
| ISSN: | 1098-5514 |
| Popis: | The preeminent mode of action of the broad-spectrum antiviral nucleoside ribavirin in the therapy of chronic hepatitis C is currently unresolved. Particularly under contest are possible mutagenic effects of ribavirin that may lead to viral extinction by lethal mutagenesis of the hepatitis C virus (HCV) genome. We applied ultradeep sequencing to determine ribavirin-induced sequence changes in the HCV coding region (nucleotides [nt] 330 to 9351) of patients treated with 6-week ribavirin monotherapy ( n = 6) in comparison to placebo ( n = 6). Baseline HCV RNA levels maximally declined on average by −0.8 or −0.1 log 10 IU/ml in ribavirin- versus placebo-treated patients. No general increase in rates of nucleotide substitutions in ribavirin-treated patients was observed. However, more HCV genome positions with high G-to-A and C-to-U transition rates were detected between baseline and treatment week 6 in ribavirin-treated patients in comparison to placebo-treated patients (rate of 0.0041 transitions per base pair versus rate of 0.0022 transitions per base pair; P = 0.049). Similarly, the sensitive detection of low-frequency minority variants by statistical filtering indicated significantly more positions with G-to-A and C-to-U transitions in ribavirin-treated patients than in placebo-treated patients (rate of 0.0331 transitions versus rate of 0.0186 transitions per G/C-containing position at baseline; P = 0.018). In contrast, non-ribavirin-associated A-to-G and U-to-C transitions were not enriched in the ribavirin group ( P = 0.152). We conclude that ribavirin exerts a mutagenic effect on the virus in patients with chronic hepatitis C by facilitating G-to-A and C-to-U nucleotide transitions. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|