HCV infection selectively impairs type I but not type III IFN signaling

Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
American Journal Of Pathology (Impact Factor: 4.59). 11/2013; 184(1). DOI: 10.1016/j.ajpath.2013.10.005
Source: PubMed


A stable and persistent Hepatitis C virus (HCV) replication cell culture model was developed to examine clearance of viral replication during long-term treatment using interferon-α (IFN-α), IFN-λ, and ribavirin (RBV). Persistently HCV-infected cell culture exhibited an impaired antiviral response to IFN-α+RBV combination treatment, whereas IFN-λ treatment produced a strong and sustained antiviral response that cleared HCV replication. HCV replication in persistently infected cells induced chronic endoplasmic reticulum (ER) stress and an autophagy response that selectively down-regulated the functional IFN-α receptor-1 chain of type I, but not type II (IFN-γ) or type III (IFN-λ) IFN receptors. Down-regulation of IFN-α receptor-1 resulted in defective JAK-STAT signaling, impaired STAT phosphorylation, and impaired nuclear translocation of STAT. Furthermore, HCV replication impaired RBV uptake, because of reduced expression of the nucleoside transporters ENT1 and CNT1. Silencing ER stress and the autophagy response using chemical inhibitors or siRNA additively inhibited HCV replication and induced viral clearance by the IFN-α+RBV combination treatment. These results indicate that HCV induces ER stress and that the autophagy response selectively impairs type I (but not type III) IFN signaling, which explains why IFN-λ (but not IFN-α) produced a sustained antiviral response against HCV. The results also indicate that inhibition of ER stress and of the autophagy response overcomes IFN-α+RBV resistance mechanisms associated with HCV infection.

Download full-text


Available from: Partha Chandra, Oct 13, 2015
49 Reads
  • Source
    • "A horseradish peroxidase-coupled antirabbit or antimouse IgG was used as secondary antibodies obtained from Cell Signaling Technology, Beverly, MA. Control siRNA (siIRR) and siRNAs against PERK and ATG7 (Life Technologies, Carlsbad, CA) were as described previously [18]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose Chronic Hepatitis C Virus (HCV)-infected patients with liver cirrhosis (LC) respond poorly to interferon-alpha (IFN-α) and ribavirin (RBV) combination therapy, but the reason for this is unclear. We previously reported that HCV-infection induces endoplasmic reticulum (ER) stress and autophagy response that selectively down regulates the type I IFN-α receptor-1 (IFNAR1) and RBV transporters (CNT1 and ENT1), leading to IFN-α/RBV resistance. The goal of this study is to verify whether an increase in ER stress and autophagy response is also associated with the reduced expression of IFNAR1 and RBV transporters in chronic HCV-infected patients. Methods Primary human hepatocytes (PHH) were infected with cell culture grown HCV particles (JFH-ΔV3-Rluc). HCV replication was confirmed by the detection of viral RNA by RT-qPCR and HCV-core protein by Western blotting. The ER stress and autophagy response and expression of IFN receptors and RBV transporters in HCV infected PHH and liver tissues derived from patients were measured by Western blotting. Result HCV infection of PHH showed impaired expression of IFNAR1, IFNγR1 (Type II IFN receptor) and RBV transporters but not IL10Rβ (Type III IFN-λ receptor). ER stress markers (BiP, IRE1α and peIF2α) and autophagy response (LC3II, Beclin 1 and ATG5) were induced in HCV infected chronic liver disease (CLD) and LC patients. Liver biopsies (CLD) show a 50% reduced expression of IFNAR1 and RBV transporters. Furthermore, the expression of IFNAR1 and RBV transporters was impaired in almost all LC patients. Conclusion HCV infection induces ER stress and autophagy response in infected PHH and chronically infected liver tissues. The expression of IFNAR1, IFNγR1 and RBV transporters were significantly impaired in CLD and cirrhotic livers. Our study provides a potential explanation for the reduced response rate of IFN-α and RBV combination therapy in HCV infected patients with liver cirrhosis.
    PLoS ONE 09/2014; 9(9):e108616. DOI:10.1371/journal.pone.0108616 · 3.23 Impact Factor
  • Source
    • "ER stress and autophagy are also involved in the inhibition of the antiviral response downstream to IFN production by downregulating the expression of type I IFN (IFN-α) receptors but not type II (IFN-γ) or type III (IFN-λ) [95]. In the same context, the expression of the nucleoside transporters ENT1 and CNT1, which are involved in the transport of the antiviral drug Ribavirin (RBV), is also decreased, thus suggesting a possible contribution of autophagy in the partial resistance to type I IFN/RBV-based therapy in vivo [95]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatitis C virus (HCV) infection is one of the main causes of chronic liver disease. Viral persistence and pathogenesis rely mainly on the ability of HCV to deregulate specific host processes, including lipid metabolism and innate immunity. Recently, autophagy has emerged as a cellular pathway, playing a role in several aspects of HCV infection. This review summarizes current knowledge on the molecular mechanisms that link the HCV life cycle with autophagy machinery. In particular, we discuss the role of HCV/autophagy interaction in dysregulating inflammation and lipid homeostasis and its potential for translational applications in the treatment of HCV-infected patients.
    BioMed Research International 08/2014; 2014:265353. DOI:10.1155/2014/265353 · 3.17 Impact Factor
  • Source
    • "Almost any cell type is able to express IFNL1–3 mRNA in response to diverse viral infections such as Sindbis virus, dengue virus, vesicular stomatitis virus, encephalomyocarditis virus,9,10 respiratory syncytial virus,30,31 influenza virus, Sendai virus32,33and hepatitis C virus (HCV).34,35,36 High levels of IFNLs, but not IFN-α, were observed during viral infection of lung and liver tissues,36,37,38,39,40,41and IFNLs seem to be the major IFNs induced in airway epithelial cells during infection with respiratory viruses.42,43,44 The most potent producers of IFNLs however, seem to be myeloid and plasmacytoid dendritic cells (DCs).27,45,46,47,48 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Type-III interferons (IFN-λ, IFNL) are the most recently described family of IFNs. This family of innate cytokines are increasingly being ascribed pivotal roles in host–pathogen interactions. Herein, we will review the accumulating evidence detailing the immune biology of IFNL during viral infection, and the implications of this novel information on means to advance the development of therapies and vaccines against existing and emerging pathogens. IFNLs exert antiviral effects via induction of IFN-stimulated genes. Common single nucleotide polymorphisms (SNPs) in the IFNL3, IFNL4 and the IFNL receptor α-subunit genes have been strongly associated with IFN-α-based treatment of chronic hepatitis C virus infection. The clinical impact of these SNPs may be dependent on the status of viral infection (acute or chronic) and the potential to develop viral resistance. Another important function of IFNLs is macrophage and dendritic cell polarization, which prime helper T-cell activation and proliferation. It has been demonstrated that IFNL increase Th1- and reduce Th2-cytokines. Therefore, can such SNPs affect the IFNL signaling and thereby modulate the Th1/Th2 balance during infection? In turn, this may influence the subsequent priming of cytotoxic T cells versus antibody-secreting B cells, with implications for the breadth and durability of the host response.
    Emerging Microbes and Infections 07/2014; 3(7). DOI:10.1038/emi.2014.51 · 2.26 Impact Factor
Show more