Interferon Response in Hepatitis C Virus-Infected Hepatocytes: Issues to Consider in the Era of Direct-Acting Antivirals

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 to in HCV-infected hepatocytes. In particular, we focused on open issues related to IFN responses in the direct-acting antiviral era.

Keywords: direct-acting antivirals; hepatitis C virus; innate immunity; interferon.

Figure 1

Induction of types I and III interferons (IFNs) in hepatitis C virus (HCV)-infected hepatocytes. After HCV enters hepatocytes, double-stranded RNA intermediates are recognized preferentially by MDA5 in the cytoplasm and by TLR3 in the endosome. LGP2 contributes to the efficacy of MDA5 in recognizing HCV RNA. HCV-induced lncRNA ITPRIP-1 stimulates the oligomerization and activation of MDA5. When MDA-5 binds to MAVS, they activate downstream NF-κB and IRF3 pathways, which lead to the induction of IFN-β, IFN-λs, and other pro-inflammatory cytokines. HCV NS3/4A protease (pictured as scissors) cleaves MAVS and partially disrupts the associated signaling. HCV NS3/4A protease also cleaves IMPβ1, which transports NF-κB from the cytoplasm to the nucleus. HCV NS4B activates caspase 8, which degrades TRIF and hampers the signal transduction from TLR3. NS4B also targets STING and blocks IRF3 phosphorylation. Despite these evasive HCV strategies, a considerable amount of IFNs are produced. Pointed arrows indicate activation; Blocked arrows indicate inhibition. IKKε: IkB kinase-ε.

Figure 2

Roles of the IFNL4 genotype in the responsiveness to exogenous IFN-α in HCV infections. (A) In patients with the IFNL4-ΔG/ΔG (rs368234815) or IFNL4-ΔG/TT genotype, IFN-λs (including IFN-λ4) and type I IFNs are produced. When type I and III IFNs bind to their receptors, they trigger the initial formation of ISGF3, which is composed of phosphorylated STAT1, phosphorylated STAT2, and IRF9. ISGF3 stimulates the expression of ISGs. After an HCV infection is established, ISG expression is maintained by U-ISGF3, which is composed of high levels of unphosphorylated STAT1, unphosphorylated STAT2, and IRF9. U-ISGF3 induces the abundant production of ISG15 in HCV-infected cells. Subsequently, ISG15 stabilizes the USP18 protein. In turn, USP18 blocks signaling through the IFN-α-bound IFNα/β receptor, which attenuates the response to exogenous IFN-α. As a result, pegylated IFN-α treatment has low efficacy. (B) In patients with the IFNL4-TT/TT (rs368234815) genotype, functional IFN-λ4 protein is not produced. In this case, U-ISGF3 is less abundant, which leads to weak ISG15 induction and low USP18 protein levels in infected hepatocytes. Consequently, the response to exogenous IFN-α is not attenuated. As a result, pegylated IFN-α has potent antiviral efficacy. Pointed arrows indicate activation; Blocked arrows indicate inhibition. Ub: ubiquitin.