Reactive oxygen species suppress hepatitis C virus RNA replication in human hepatoma cells.
Hepatitis C virus (HCV) is a positive-stranded RNA virus that causes severe liver diseases, such as cirrhosis and hepatocellular carcinoma. HCV uses an RNA-dependent RNA polymerase to replicate its genome and an internal ribosomal entry site to translate its proteins. HCV infection is characterized by an increase in the concentrations of reactive oxygen species (ROS), the effect of which on HCV replication has yet to be determined. In this report, we investigated the effect of ROS on HCV replication, using a bicistronic subgenomic RNA replicon and a genomic RNA that can replicate in human hepatoma cells. The treatment with peroxide at concentrations that did not deplete intracellular glutathione or induce cell death resulted in significant decreases in the HCV RNA level in the cells. This response could be partially reversed by the antioxidant N-acetylcysteine. Further studies indicated that such a suppressive response to ROS was not due to the suppression of HCV protein synthesis or the destabilization of HCV RNA. Rather, it occurred rapidly at the level of RNA replication. ROS appeared to disrupt active HCV replication complexes, as they reduced the amount of NS3 and NS5A in the subcellular fraction where active HCV RNA replication complexes were found. In conclusion, our results show that ROS can rapidly inhibit HCV RNA replication in human hepatoma cells. The increased ROS levels in hepatitis C patients may therefore play an important role in the suppression of HCV replication.
Choi
Jinah
J
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Lee
Ki Jeong
KJ
Zheng
Yanyan
Y
Yamaga
Ardath K
AK
Lai
Michael M C
MM
Ou
Jing-Hsiung
JH
D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor / Q000821:virology; D016174:Hepacivirus / Q000235:genetics / Q000254:growth & development*; D006526:Hepatitis C / Q000378:metabolism* / Q000821:virology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008113:Liver Neoplasms; D016877:Oxidants / Q000494:pharmacology; D012367:RNA, Viral / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013347:Subcellular Fractions / Q000821:virology; D014779:Virus Replication / Q000187:drug effects
D016877:Oxidants; D012367:RNA, Viral; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide