Activation of the Interferon-Inducible 2′-5′-Oligoadenylate Synthetase Gene by Hepatitis C Virus Core Protein

Naganuma, Atsushi; Nozaki, Akira; Tanaka, Torahiko; Sugiyama, Kazuo; Takagi, Hitoshi; Mori, Masataka; Shimotohno, Kunitada; Kato, Naoya

doi:10.1128/jvi.74.18.8744-8750.2000

Cited by 69 publications

(58 citation statements)

References 52 publications

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“…Data from different groups indicate that core protein modulates the IFN-induced Jak/STAT signaling pathway but does not affect the activation of some ISGs. In contrast, other reports showed a downregulation of interferoninduced antiviral genes (3,12,54).…”

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confidence: 42%

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

Ciccaglione

Stellacci

Marcantonio

et al. 2007

J Virol

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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...

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contrasting

confidence: 42%

“…Conversely, (3,6,7,12,47,48,50,54). Variations in the experimental system used, structural or genotypic differences in the protein and, possibly, the amount of protein used may all be implicated in the reported discrepancies.…”

Section: Discussionmentioning

confidence: 82%

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

Ciccaglione

Stellacci

Marcantonio

et al. 2007

J Virol

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“…Thus, the core protein of hepatitis C virus can directly activate OAS expression, presumably to moderate viral replication (40), and the precore and core proteins of hepatitis B virus directly down-regulate MxA expression by binding to both of the ISREs that control IFN-induced expression of MxA (41). Hepatitis B virus-mediated regulation of MxA expression appears to be at work in vivo as well, because chronically infected hepatitis B virus patients with high levels of viral replication have low levels of IFN-induced MxA, while other ISGs such as OAS are expressed at high levels (41).…”

Section: Discussionmentioning

confidence: 99%

Interferon-Induced Expression of MxA in the Respiratory Tract of Rhesus Macaques Is Suppressed by Influenza Virus Replication

Carroll

Matzinger

Genescà

et al. 2008

The Journal of Immunology

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To determine the relationship between influenza A virus replication and innate antiviral immune responses, rhesus monkeys were given oseltamivir before influenza A/Memphis/7/01 (H1N1) challenge. We found that oseltamivir treatment significantly reduced viral replication in the trachea (p < 0.029). Further, in the trachea of both treated and untreated monkeys the mRNA levels of most innate antiviral molecules in the IFN-αβ pathway were dramatically increased by 24 h postinfection. However, the mRNA level of a single IFN-stimulated gene, MxA (myxovirus resistance A), the IFN-stimulated gene known to be critical in blocking influenza virus replication, was significantly lower in the tracheal lavages of untreated monkeys than in the oseltamivir-treated monkeys (p = 0.05). These results demonstrate for the first time that uncontrolled influenza A virus replication actively suppresses MxA gene expression and emphasize the critical role of innate immunity in controlling influenza virus replication in vivo.

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“…9 HepG2 and PH5CH8 (human immortalized hepatocytes) cells were cultured as previously described. 14,15 Luciferase Reporter Assay. For the renilla luciferase (RL) assay, 2 ϫ 10 4 OR6 cells were plated in 24-well plates at least in triplicate for each assay and were cultured for 24 hours.…”

Section: Methodsmentioning

confidence: 99%

Different anti-HCV profiles of statins and their potential for combination therapy with interferon

et al. 2006

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We recently developed a genome-length hepatitis C virus (HCV) RNA replication system (OR6) with luciferase as a reporter. The OR6 assay system has enabled prompt and precise quantification of HCV RNA replication. Pegylated interferon (IFN) and ribavirin combination therapy is the world standard for chronic hepatitis C, but its effectiveness is limited to about 55% of patients. Newer therapeutic approaches are needed. In the present study, we used the OR6 assay system to evaluate the anti-HCV activity of 3-hydroxy-3-methylglutaryl coenzyme A ( P ersistent hepatitis C virus (HCV) infection causes liver fibrosis and hepatocellular carcinoma. Approximately 170 million people worldwide are infected with HCV. The combination of pegylated interferon (IFN) with ribavirin is the current standard therapy for chronic hepatitis C (CHC) and yields a sustained virological response (SVR) rate of about 55%. 1 This means that about 45% of patients with CH C are still threatened by the progression of the disease to cirrhosis and hepatocellular carcinoma. Until 1999, when Lohmann et al. developed the subgenomic replicon of HCV, it was difficult to screen anti-HCV reagents. 2 Many improvements followed that breakthrough, such as a genome-length HCV RNA replication system 3,4 and a subgenomic replicon with a reporter assay system 5 ; more recently, Wakita et al. used a genotype 2a strain, JFH1, to produce the infectious virus in cell culture. [6][7][8] Genotype 1 is the major genotype of HCV found in Japan, the United States, and many other countries. Unfortunately, the SVR rate after combination therapy of pegylated IFN with ribavirin is less than 50% for this genotype. To find a more effective therapy especially for CHC patients with genotype 1, we recently developed a genome-length HCV RNA (strain O of genotype 1b) replication reporter system (OR6), which has been an effective screening tool. 9,10 Statins, which are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are in wide use for the treatment of hypercholesterolemia. Recently, it

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Activation of the Interferon-Inducible 2′-5′-Oligoadenylate Synthetase Gene by Hepatitis C Virus Core Protein

Cited by 69 publications

References 52 publications

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

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

Interferon-Induced Expression of MxA in the Respiratory Tract of Rhesus Macaques Is Suppressed by Influenza Virus Replication

Different anti-HCV profiles of statins and their potential for combination therapy with interferon

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