Heme oxygenase-1 suppresses hepatitis C virus replication and increases resistance of hepatocytes to oxidant injury.
Oxidative injury to hepatocytes occurs as a result of hepatitis C virus (HCV) infection and replication. Modulation of host cell antioxidant enzymes such as heme oxygenase-1 (HO-1) may be useful therapeutically to minimize cellular injury, reduce viral replication, and attenuate liver disease. In this report, we evaluated the effects of HO-1 overexpression on HCV replication and hepatocellular injury. Full-length (FL) (Con1) or nonstructural (NS) replicons (I 389 NS3-3') were transfected with complete human HO-1 sequences or empty vector for control. Cell lines overexpressing HO-1 (twofold to sixfold above basal values) or empty vector were isolated, and their HCV RNA synthesis, pro-oxidant levels, and resistance to oxidative injury were assessed. HO-1 overexpression decreased HCV RNA replication in both FL and NS replicons without affecting cellular growth or DNA synthesis. The attenuation of HCV replication was significantly reversed in both replicon systems with HO-1 small interfering RNA (siRNA) knockdown. Both FL and NS replicons that overexpress HO-1 showed reduced prooxidant levels at baseline and increased resistance to oxidant-induced cytotoxicity. HO-1 induction with hemin also markedly decreased HCV replication in both parental FL and NS replicon cell lines. Conversely, knockdown of HO-1 messenger RNA (mRNA) by siRNA in parental FL or NS replicons did not significantly affect HCV replication, suggesting that less than basal levels of HO-1 had minimal effect on HCV replication.


CONCLUSIONS
Overexpression or induction of HO-1 results in decreased HCV replication as well as protection from oxidative damage. These findings suggest a potential role for HO-1 in antiviral therapy and therapeutic protection against hepatocellular injury in HCV infection.
Zhu
Zhaowen
Z
Department of Internal Medicine and Research Service, Veterans Administration Medical Center, University of Iowa, Iowa City, IA, USA.
Wilson
Anne T
AT
Mathahs
M Meleah
MM
Wen
Feng
F
Brown
Kyle E
KE
Luxon
Bruce A
BA
Schmidt
Warren N
WN
D006528:Carcinoma, Hepatocellular; D002455:Cell Division; D045744:Cell Line, Tumor; D017931:DNA Primers; D051547:Heme Oxygenase-1 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008113:Liver Neoplasms; D016877:Oxidants / Q000633:toxicity*; D034741:RNA, Small Interfering / Q000235:genetics; D012093:Replicon / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014779:Virus Replication / Q000187:drug effects; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
D017931:DNA Primers; D016877:Oxidants; D034741:RNA, Small Interfering; D020122:tert-Butylhydroperoxide; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1