H epatitis C virus (HCV) is one of the most important pathogens causing liver-related morbidity and mortality. 1 Hepatitis C is characterized by persistent infection of the liver, leading to the development of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Type-I interferon (IFN) plays a central role in eliminating viruses, not only by way of therapeutic applications 2 but also as a natural cellular antiviral mechanism. 3,4 Interferons are produced naturally in response to virus infection and to cellular exposure to IFN itself. Binding of the IFNs to their receptors activates the Jak-STAT pathway to form a complex with IFN-stimulated gene factor-3 (ISGF3), which translocates to the nucleus, binds the IFN-stimulated response element (ISRE) located in the promoter/enhancer region of the IFN-stimulated genes (ISGs), and activates expression of ISGs.HCV subgenomic replicons constitute in-vitro models that simulate cellular autonomous replication of HCV

Substitution of amino acids 70 and 91 in the hepatitis C virus (HCV) core region is a significant predictor of poor responses to peginterferon-plus-ribavirin therapy, while their molecular mechanisms remain unclear. Here we investigated these differences in the response to alpha interferon (IFN) by using HCV cell culture with R70Q, R70H, and L91M substitutions. IFN treatment of cells transfected or infected with the wild type or the mutant HCV clones showed that the R70Q, R70H, and L91M core mutants were significantly more resistant than the wild type. Among HCV-transfected cells, intracellular HCV RNA levels were significantly higher for the core mutants than for the wild type, while HCV RNA in culture supernatant was significantly lower for these mutants than for the wild type. IFN-induced phosphorylation of STAT1 and STAT2 and expression of the interferon-inducible genes were significantly lower for the core mutants than for the wild type, suggesting cellular unresponsiveness to IFN. The expression level of an interferon signal attenuator, SOCS3, was significantly higher for the R70Q, R70H, and L91M mutants than for the wild type. Interleukin 6 (IL-6), which upregulates SOCS3, was significantly higher for the R70Q, R70H, and L91M mutants than for the wild type, suggesting interferon resistance, possibly through IL-6-induced, SOCS3-mediated suppression of interferon signaling. Expression levels of endoplasmic reticulum (ER) stress proteins were significantly higher in cells transfected with a core mutant than in those transfected with the wild type. In conclusion, HCV R70 and L91 core mutants were resistant to interferon in vitro, and the resistance may be induced by IL-6-induced upregulation of SOCS3. Those mechanisms may explain clinical interferon resistance of HCV core mutants.Hepatitis C virus (HCV) is one of the most important pathogens causing liver-related morbidity and mortality. Approximately 3% of the worldwide population is infected with HCV, which represents 170 million people, and 3 million to 4 million individuals are newly infected each year (33,47,62). There is no therapeutic or prophylactic vaccine available for HCV. Antiviral treatment has been shown to improve liver histology and decrease the incidence of hepatocellular carcinoma in chronic hepatitis C (CHC) (17, 64). Current therapies for CHC consist of treatment with pegylated interferon (peg-IFN), which acts both as an antiviral and as an immunoregulatory cytokine, and ribavirin (RBV), an antiviral prodrug that interferes with RNA metabolism (16, 31). However, less than 50% of patients infected with HCV genotype 1 treated in this way achieve a sustained virological response (SVR) or a cure of the infection (14, 16). Given this situations, gaining a detailed understanding of the molecular mechanisms of interferon (IFN) resistance has been a high priority in academia and industry.The response to peg-IFN-plus-RBV treatment is affected by several viral and host factors, including age, gender (22, 23), grade of liver fibrosis (21, 42), HCV ge...

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Comprehensive gene expression and pathway analyses show that lipid biosynthesis pathways are crucial to support proficient virus replication. These metabolic pathways could constitute novel antiviral targets against HCV.

Mechanisms of difference in interferon sensitivity between hepatitis C virus (HCV) strains have yet to be clarified. Here, we constructed an infectious genotype2b clone and analyzed differences in interferon-alpha sensitivity between HCV-2b and 2a-JFH1 clones using intergenotypic homologous recombination. The HCV-2b/JFH1 chimeric virus able to infect Huh7.5.1 cells and was significantly more sensitive to IFN than JFH1. IFN-induced expression of MxA and 25-OAS was significantly lower in JFH1 than in 2b/JFH1-infected cells. In JFH1-infected cells, expression of SOCS3 and its inducer, IL-6, was significantly higher than in 2b/JFH1-infected cells. The IFN-resistance of JFH1 cells was negated by siRNA-knock down of SOCS3 expression and by pretreatment with anti-IL6 antibody. In conclusion, intergenotypic differences of IFN sensitivity of HCV may be attributable to the sequences of HCV structural proteins and can be determined by SOCS3 and IL-6 expression levels.