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Ethanol and both Endogenous and Exogenous Reactive Species Accelerate the Mutation Rate of Hepatitis C Virus RNA
Author(s) -
Seronello Scott,
Presleigh Kristen,
Barlow Miriam,
Choi Jinah
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.lb74
Subject(s) - rna , hepatitis c virus , ns5a , rna virus , rna dependent rna polymerase , mutation rate , biology , nonsynonymous substitution , population , replicon , virology , mutation , virus , chemistry , biochemistry , hepacivirus , gene , medicine , genome , environmental health
Hepatitis C virus (HCV) demonstrates a high level of genetic variability existing as a population of closely related but distinct genetic variants, referred to as quasispecies. Ethanol intake is one of the major cofactors in HCV‐induced pathogenesis and is correlated with increased sequence heterogeneity of HCV RNA in patients, which is likely to promote viral persistence and complicate anti‐HCV therapy. However, the mechanism underlying this interaction between HCV and ethanol is unknown. The purpose of this study was to examine whether ethanol and endogenous and exogenous reactive species can increase the mutation rate of HCV. The NS5A region of Con1 HCV replicon RNA was sequenced after treatment with ethanol, acetaldehyde, exogenous hydrogen peroxide, and L‐buthionine‐S,R‐sulfoximine, which accelerated the mutation rate of HCV RNA over that of the control group within 48 hrs. The dn/ds ratio also increased significantly with the nonsynonymous mutations clustering in the C‐terminal half of NS5A. Half of amino acid substitutions involved serine, threonine, or tyrosine, suggesting possible changes in NS5A phosphorylation. The treatments also induced RNA damage. Therefore, ethanol may synergize with virus‐induced oxidative/nitrosative stress to induce RNA damage that amplifies the error rate of the viral replicase increasing the heterogeneity of HCV RNA. This work was supported by funds from UC Merced.