Hepatitis C virus inhibits intracellular interferon alpha expression in human hepatic cell lines.
The chronicity of hepatitis C virus (HCV) infection raises the question of how HCV is able to persist in hepatic cells. We show that human primary hepatocytes and human hepatic cell lines (Huh7 and HepG2) spontaneously produce interferon (IFN)-alpha that is inhibited in the HCV replicon cells (Huh.8 and FCA-1). Silencing IFN-alpha gene expression by IFN-alpha small interfering RNA (siRNA) in the HCV replicon cells resulted in increased HCV replicon expression. The activation of IFN-alpha expression by interferon regulatory factor (IRF-7) led to the inhibition of HCV replicon expression, whereas the anti-IFN-alpha receptor antibody could partially block IRF-7-mediated HCV replicon inhibition. In addition, the blockade of IFN-alpha receptor by anti-IFN-alpha receptor antibody on the replicon cells increased HCV replicon expression. Among the HCV nonstructural (NS) proteins tested, NS5A is the most potent inhibitor of IFN-alpha expression by the hepatic cells. Investigation of the mechanism of HCV action on IFN-alpha showed that IRF-7-induced IFN-alpha promoter activation was inhibited in the HCV replicon cells. Furthermore, IRF-7 expression was restricted in the HCV replicon cells. In conclusion, we provide direct evidence that HCV undermines the intracellular innate immunity of the target cells, which may account for HCV persistence in hepatic cells.
Zhang
Ting
T
Division of Allergy & Immunology, Joseph Stokes Jr. Research Institute at The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Lin
Rong-Tuan
RT
Li
Yuan
Y
Douglas
Steven D
SD
Maxcey
Catherine
C
Ho
Chun
C
Lai
Jian-Ping
JP
Wang
Yan-Jian
YJ
Wan
Qi
Q
Ho
Wen-Zhe
WZ
D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D020868:Gene Silencing; D016174:Hepacivirus / Q000235:genetics* / Q000254:growth & development / Q000276:immunology; D006526:Hepatitis C / Q000276:immunology* / Q000821:virology*; D022781:Hepatocytes / Q000166:cytology / Q000821:virology*; D006801:Humans; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha / Q000235:genetics*; D011401:Promoter Regions, Genetic; D014779:Virus Replication / Q000276:immunology
D004268:DNA-Binding Proteins; C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha