Abstract
When interferons (IFNs) bind to their receptors, they upregulate numerous IFN-stimulated genes (ISGs) with antiviral and immune regulatory activities. Hepatitis C virus (HCV) is a single-stranded, positive-sense RNA virus that affects over 71 million people in the global population. Hepatocytes infected with HCV produce types I and III IFNs. These endogenous IFNs upregulate a set of ISGs that negatively impact the outcome of pegylated IFN-α and ribavirin treatments, which were previously used to treat HCV. In addition, the IFNL4 genotype was the primary polymorphism responsible for a suboptimal treatment response to pegylated IFN-α and ribavirin. However, recently developed direct-acting antivirals have demonstrated a high rate of sustained virological response without pegylated IFN-α. Herein, we review recent studies on types I and III IFN responses in HCV-infected hepatocytes. In particular, we focused on open issues related to IFN responses in the direct-acting antiviral era.
Highlights
Interferons (IFNs) have critical antiviral activities and immune regulatory functions in infections and autoimmunity
Types I and III IFNs mainly drive the formation of STAT1-STAT2 heterodimers, which bind to interferon regulatory factor 9 (IRF9); together, these proteins form a complex known as interferon-stimulated gene factor 3 (ISGF3) [31]
IFN production and IFN-stimulated genes (ISGs) upregulation occur in hepatocytes after Hepatitis C virus (HCV) infections, HCV interferes with this process (Figure 1) [10]
Summary
Interferons (IFNs) have critical antiviral activities and immune regulatory functions in infections and autoimmunity These IFN functions are mediated by inducing the expression of various IFN-stimulated genes (ISGs) [1]. Types I and III IFNs are similar in their induction mechanisms and in the intracellular signaling pathways that lead to ISG expression They use different receptors and are encoded by distinct genes [2]. HCV-infected hepatocytes produce types I and III IFNs, which leads to the prolonged upregulation of ISGs in HCV-infected livers [10,11,15,16,17,18,19,20,21]. This review covers the recent progress on types I and III IFN responses in hepatocytes and their roles in HCV infections. Canonical and Non-Canonical Types I and III IFN Signaling Pathways in Hepatocytes
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