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

Immunological Mechanisms for Hepatocellular Carcinoma Risk after Direct-Acting Antiviral Treatment of Hepatitis C Virus Infection

“…In the HCV-infected liver, type I and III IFNs produced in the infected liver are not sufficient to eliminate HCV infection. Moreover, HCV successfully replicates even when high IFN-stimulated gene (ISG) expression levels are sustained [ 40 , 41 ]. This upregulated expression of ISGs has been shown to negatively affect the outcome of peg-IFN-α and ribavirin treatments [ 7 , 41 ].…”

“…This upregulated expression of ISGs has been shown to negatively affect the outcome of peg-IFN-α and ribavirin treatments [ 7 , 41 ]. The IFNL4 genotype, which determines whether functionally active IFN-λ4 protein is produced, is the primary polymorphism explaining the unsuccessful responses to IFN-α-based therapy [ 7 , 40 ]. The allele that codes for the production of the fully active form of IFN-λ4, rs368234815-ΔG, is directly associated with ISG upregulation in the livers of HCV-infected patients [ 40 ].…”

microRNA-99a Restricts Replication of Hepatitis C Virus by Targeting mTOR and De Novo Lipogenesis

“…Worldwide, approximately 71 million people are infected with hepatitis C virus (HCV), and they have an increased risk of liver cirrhosis and hepatocellular carcinoma (HCC) [ 1 , 2 , 3 ]. The viral life cycle of HCV strongly depends on intracellular lipid droplets (LDs) [ 4 ].…”

Ribosome Pausing at Inefficient Codons at the End of the Replicase Coding Region Is Important for Hepatitis C Virus Genome Replication

“…The resulting liver-derived mixed lipo-viro particles serve to hide the virus from the immune system and to enhance uptake of the viral particles by the next hepatocyte host cell by the use of apolipoproteins [ 6 , 10 , 13 ]. Moreover, HCV has developed several strategies to counteract the immune response [ 14 , 15 , 16 ], including the use of cellular long non-coding RNAs [ 17 , 18 ]. Chronic HCV infection is often recognized only accidentally, e.g., during hospitalization, a reason why virus spread in the population is often unnoticed [ 14 , 15 ].…”