Repression of Interferon Regulatory Factor 1 by Hepatitis C Virus Core Protein Results in Inhibition of Antiviral and Immunomodulatory Genes

Abstract

Hepatitis C virus (HCV) proteins are known to interfere at several levels with both innate and adaptive responses of the host. A key target in these effects is the interferon (IFN) signaling pathway. While the effects of nonstructural proteins are well established, the role of structural proteins remains controversial. We investigated the effect of HCV structural proteins on the expression of interferon regulatory factor 1 (IRF-1), a secondary transcription factor of the IFN system responsible for inducing several key antiviral and immunomodulatory genes. We found substantial inhibition of IRF-1 expression in cells expressing the entire HCV replicon. Suppression of IRF-1 synthesis was mainly mediated by the core structural protein and occurred at the transcriptional level. The core protein in turn exerted a transcriptional repression of several interferonstimulated genes, targets of IRF-1, including interleukin-15 (IL-15), IL-12, and low-molecular-mass polypeptide 2. These data recapitulate in a unifying mechanism, i.e., repression of IRF-1 expression, many previously described pathogenetic effects of HCV core protein and suggest that HCV core-induced IRF-1 repression may play a pivotal role in establishing persistent infection by dampening an effective immune response.Infection with hepatitis C virus (HCV) represents the major cause of liver disease, affecting more than 170 million individuals worldwide (26). After a subclinical phase, more than 80% of patients progress to persistent HCV infection, which is the leading cause of chronic liver disease associated with cirrhosis and hepatocellular carcinoma (13). The persistence of the virus in the majority of infected individuals is linked to the ability of HCV to evade and/or antagonize the host immune response at both the local and systemic levels. Accordingly, although hepatocytes are a major target of HCV infection, the virus can also replicate in immune cells, including effector cells (1,11). In this respect, resistance to interferon (IFN) therapy is a hallmark of evolution in persistence, indicating that knocking down the antiviral and immunomodulating effects of IFN is a successful strategy for evading the host immune surveillance (21). The production and secretion of IFN type I is pivotal in inducing a global antiviral state through paracrine IFN production and the subsequent activation of interferon-stimulated genes (ISGs) within the infected cells and in the surrounding tissues (70). The role of IFN in HCV infection is thus crucial (21). Functional genomic analyses from cohorts of human subjects with chronic infection have shown that infection is associated with a gene expression profile marked by ISGs whose level of expression is related to different degrees of liver fibrosis and cirrhosis (67). Similarly, gene expression profiling has demonstrated that acute resolving infections in chimpanzees are associated with high levels of hepatic ISG expression (4).The single-stranded RNA genome of HCV is translated into a polypeptide precursor of 3,010 amino aci...

Hepatitis C Virus-Mediated Inhibition of Cathepsin S Increases Invariant-Chain Expression on Hepatocyte Surface

“…Subsequent studies by Kanazawa et al (27) have shown that suppression of IRF-1 mRNA expression occurs in HCV replicon-harboring cells, while Huh7 cells with the replicon eliminated (cured) display IRF-1 expression, implying replicon genome replication or viral protein expression in replicon-harboring cells suppresses IRF-1 expression. On the other hand, Ciccaglione et al (15) reported that the expression levels of IRF-1 were decreased in clones harboring the full-length-HCV genome, and our results presented here are very similar. The minor differences in all these observations could be due to the expression levels of viral proteins in different cell types and the genotypes of virus used.…”

Identification and characterization of interferon regulatory factor-1 from orange-spotted grouper (Epinephelus coioides)

“…As a member of the interferon regulatory factor family, IRF-1 was originally identified as a regulator of the IFNa/b promoter but later recognized to regulate several IFN-stimulated genes (ISGs) as well by binding the IFN-stimulated response element (ISRE) in the IFN-a/ b-stimulated gene promoters and thus amplify the IFN response [29,30]. IRF-1 is a regulator not only of cellular antiviral responses through the induction of antiviral ISGs, including 2-5A synthetase and PKR, but also of cellular apoptosis and transformation and immune responses through the regulation of many specific target genes [31]. Because of its key role in IFN immune system, IRF-1 has been identified from several species including mammals, avians, amphibians and teleosts.…”

Adenylate cycalse toxin ofBordetella pertussisinhibits TLR-induced IRF-1 and IRF-8 activation and IL-12 production and enhances IL-10 through MAPK activation in dendritic cells

“…However, recent reports have suggested that IFN-regulatory factors (IRF), which mediate antiviral responses through transcription of IFN genes, also play a critical role in signaling for IL-12 production. It has been demonstrated that expression of hepatitis C virus core protein suppresses IRF-1 and IL-12 promoter activity in Huh-7 cells [17]. Furthermore, it has been reported that infection of human DC with a mutant B. pertussis lacking CyaA enhanced expression of IRF-1 and IRF-8 over that seen with the wild-type bacteria [18].…”