To guard against viral infection, the host cell has developed multiple restriction strategies to limit viral infection. 15, 16 With the ability to enhance the immune response for virus clearance or to inhibit viral replication, IFN-based therapies have been used to treat HCV-infected patients for over two decades. These cytokines confer an antiviral state on the host cells, thereby interfering with viral replication. In the competition between this virus and host cells, viral infection often triggers a first-line host defense through the production of type I interferon (IFN), which is a broadly acting antiviral cytokine, and inflammatory cytokines. For instance, infection with HCVcc or expression of the Japanese fulminant hepatitis-1 genome has been shown to trigger cytopathic effects, endoplasmic reticulum (ER) stress, the unfolded protein response (UPR), autophagy and the innate immune response. In this coevolution process, HCV exhibits multifaceted interactions with the host cells, and these cellular stress responses subsequently affect virus replication. 6 demonstrated that HCV and cells coevolve in vitro during chronically persistent infection, which involves the selection of viral mutants with increased infectivity and cells with resistance to viral entry and/or RNA replication. Using the HCV genotype 2a isolate Japanese fulminant hepatitis-1 genome-based cell culture-derived infectious HCV (HCVcc), 5 Zhong et al. 2, 3 Furthermore, HCV is a major cause of type I mixed cryoglobulinemia, which occurs in 10% of patients. 1 Acute HCV infection is asymptomatic, and in 70% of infected individuals, the virus persists and progresses to chronic liver diseases, including fibrosis, steatosis, cirrhosis and hepatocellular carcinoma. Hepatitis C virus (HCV) infects more than 170 million people worldwide and represents a heavy burden to global health, with the highest prevalence rates found in Africa and the Eastern Mediterranean. Elucidation of the specificity and the mode of action of these emerging ISGs will also help to identify novel cellular targets against which effective HCV therapeutics can be developed. This review will provide a basis for understanding the complexity and functionality of the pleiotropic IFN system in HCV infection. Finally, we discuss the functions of several cellular determinants critical for regulating host immunity in HCV replication. We also highlight the potential functions of emerging ISGs, which were identified from genome-wide siRNA screens, in HCV replication. Then, we summarize the effector mechanisms of scaffold ISGs known to modulate IFN function in HCV replication. In this review, we first outline the signaling pathways known to be involved in the production of type I IFN and ISGs and the tactics that HCV uses to subvert innate immunity. Nevertheless, the mechanisms by which these ISGs participate in IFN-mediated anti-HCV actions remain largely unknown. Type I IFN elicits its antiviral actions by inducing a wide array of IFN-stimulated genes (ISGs). Conversely, HCV employs diverse strategies to escape host innate immune surveillance. Upon HCV infection, the host induces the interferon (IFN)-mediated frontline defense to limit virus replication. HCV infection strongly induces host responses, such as the activation of the unfolded protein response, autophagy and the innate immune response. Infection with hepatitis C virus (HCV), a major viral cause of chronic liver disease, frequently progresses to steatosis and cirrhosis, which can lead to hepatocellular carcinoma.
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