Abstract
PurposeChronic Hepatitis C Virus (HCV)-infected patients with liver cirrhosis (LC) respond poorly to interferon-alpha (IFN-α) and ribavirin (RBV) combination therapy, but the reason for this is unclear. We previously reported that HCV-infection induces endoplasmic reticulum (ER) stress and autophagy response that selectively down regulates the type I IFN-α receptor-1 (IFNAR1) and RBV transporters (CNT1 and ENT1), leading to IFN-α/RBV resistance. The goal of this study is to verify whether an increase in ER stress and autophagy response is also associated with the reduced expression of IFNAR1 and RBV transporters in chronic HCV-infected patients.MethodsPrimary human hepatocytes (PHH) were infected with cell culture grown HCV particles (JFH-ΔV3-Rluc). HCV replication was confirmed by the detection of viral RNA by RT-qPCR and HCV-core protein by Western blotting. The ER stress and autophagy response and expression of IFN receptors and RBV transporters in HCV infected PHH and liver tissues derived from patients were measured by Western blotting.ResultHCV infection of PHH showed impaired expression of IFNAR1, IFNγR1 (Type II IFN receptor) and RBV transporters but not IL10Rβ (Type III IFN-λ receptor). ER stress markers (BiP, IRE1α and peIF2α) and autophagy response (LC3II, Beclin 1 and ATG5) were induced in HCV infected chronic liver disease (CLD) and LC patients. Liver biopsies (CLD) show a 50% reduced expression of IFNAR1 and RBV transporters. Furthermore, the expression of IFNAR1 and RBV transporters was impaired in almost all LC patients.ConclusionHCV infection induces ER stress and autophagy response in infected PHH and chronically infected liver tissues. The expression of IFNAR1, IFNγR1 and RBV transporters were significantly impaired in CLD and cirrhotic livers. Our study provides a potential explanation for the reduced response rate of IFN-α and RBV combination therapy in HCV infected patients with liver cirrhosis.
Highlights
Hepatitis C virus (HCV) infection affects 150–200 million individuals worldwide [1,2] and leads to a high rate of chronic liver diseases (CLD), which often progresses to liver cirrhosis (LC) and hepatocellular carcinoma (HCC)
The expression of IFN-a receptor-1 (IFNAR1), IFN-c receptor-chain 1 (IFNcR1) and RBV transporters were significantly impaired in CLD and cirrhotic livers
Our study provides a potential explanation for the reduced response rate of IFN-a and RBV combination therapy in HCV infected patients with liver cirrhosis
Summary
Hepatitis C virus (HCV) infection affects 150–200 million individuals worldwide [1,2] and leads to a high rate of chronic liver diseases (CLD), which often progresses to liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Combination therapy of interferon (IFN)-a and ribavirin (RBV) with either a protease or polymerase inhibitor is the prevalent treatment option for chronic HCV infection. This newly-approved therapy has improved HCV clearance rate, the treatment response has not improved among individuals who are initially non-responders to IFN-a and RBV [6,7] therapy. We propose that a better understanding of IFN-a and RBV resistance mechanisms would help us improve viral clearance and reduce the risk of HCV-associated liver disease
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