Abstract
Background and AimThe interaction between hepatitis C virus (HCV) and innate antiviral defense systems in primary human hepatocytes is not well understood. The objective of this study is to examine how primary human hepatocytes response to HCV infection.MethodsAn infectious HCV isolate JFH1 was used to infect isolated primary human hepatocytes. HCV RNA or NS5A protein in the cells was detected by real-time PCR or immunofluorescence staining respectively. Apoptosis was examined with flow cytometry. Mechanisms of HCV-induced IFN-β expression and apoptosis were determined.ResultsPrimary human hepatocytes were susceptible to JFH1 virus and released infectious virus. IFN-α inhibited viral RNA replication in the cells. IFN-β and interferon-stimulated genes were induced in the cells during acute infection. HCV infection induced apoptosis of primary human hepatocytes through the TRAIL-mediated pathway. Silencing RIG-I expression in primary human hepatocytes inhibited IFN-β and TRAIL expression and blocked apoptosis of the cells, which facilitated viral RNA replication in the cells. Moreover, HCV NS34A protein inhibited viral induced IFN-β expression in primary human hepatocytes.ConclusionInnate host response is intact in HCV-infected primary human hepatocytes. RIG-I plays a key role in the induction of IFN and TRAIL by viruses and apoptosis of primary human hepatocytes via activation of the TRAIL-mediated pathway. HCV NS34A protein appears to be capable of disrupting the innate antiviral host responses in primary human hepatocytes. Our study provides a novel mechanism by which primary human hepatocytes respond to natural HCV infection.
Highlights
Hepatitis C virus (HCV) infection is a rapidly increasing public health problem, with an estimated 170 million infected patients worldwide [1]
Our study shows that infectious hepatitis C virus (HCV) can induce innate immune responses in primary human hepatocytes (PHH) via induction of IFN and triggering apoptosis of infected cells
HCV NS34A protein appears to be capable of disrupting the innate antiviral host responses in primary human hepatocytes
Summary
Hepatitis C virus (HCV) infection is a rapidly increasing public health problem, with an estimated 170 million infected patients worldwide [1]. It causes significant liver disease ranging from chronic hepatitis to cirrhosis and even hepatocellular carcinoma [2]. Around 25% to 50% of HCV infected patients resolve acute HCV infection without treatment [1], indicating that innate and/or adaptive immune responses are capable of controlling the outcome of HCV infection. The interaction between hepatitis C virus (HCV) and innate antiviral defense systems in primary human hepatocytes is not well understood. The objective of this study is to examine how primary human hepatocytes response to HCV infection
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