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Chronic hepatitis C virus (HCV) infection is a progressive disease that may end in liver cirrhosis and hepatocellular carcinoma (2). Interferon-α (IFN-α) alone or in combination with ribavirin is the only currently approved treatment for HCV infection (5). The activity against viruses of IFN is mainly mediated via the Jak-STAT (signal transducer and activator of transcription) signaling pathway. Following binding of IFN to the IFN receptor complex, Jak1 and Tyk2 kinases are activated and in turn phosphorylate STAT1 and STAT2. Phosphorylated STAT1 (P-STAT1), toge-ther with phosphorylated STAT2, and interferon regu-latory factor 9 (IRF-9) form a heterotrimeric complex, IFN-stimulated gene (ISG) factor 3 (ISGF3). ISGF3 then binds to the interferon-stimulated response element (ISRE) sequence in ISGs promoters. Thus, several antiviral proteins are induced, such as MxA, double-stranded RNA-activated protein kinase (PKR), and 2'-5'oligoadenylate synthetase (2'-5'OAS) (7, 13). Previous studies show that the activated Jak/STAT pathway was well balanced by another family of negative regulators, suppressors of cytokine signaling (SOCSs), including SOCS1 and SOCS3, which affect cytokine signaling by inhibiting phosphorylation of STAT factors (12).
HCV core protein, which is involved in forming the viral nucleocapsids, can affect a whole array of host cell function, including apoptosis, cell transformation, signal transduction, and transcriptional regulation (8, 10, 11). However, the role of HCV core protein in modulating IFN-induced ISGs expression is more controversial. 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 (1). In contrast, other authors have re-ported HCV core protein mediated activation of 2'-5'OAS gene transcription (9). Thus, whether HCV core protein interferes with expression of IFN-induced antiviral genes and whether this interference is involved in the activation and negative regulation of Jak/STAT signaling pathway remain to be demon-strated.
Effect of Hepatitis C Virus Core Protein on Interferon-Induced Antiviral Genes Expression and Its Mechanisms
- Received Date: 10 April 2007
- Accepted Date: 08 June 2007
Abstract: Emerging data indicated that HCV subverts the antiviral activity of interferon (IFN); however, whether HCV core protein contributes to the process remains controversial. In the present study, we examined the effect of HCV core protein on interferon-induced antiviral gene expression and whether the effect is involved in the activation and negative regulation of the Jak/STAT signaling pathway. Our results showed that, following treatment with IFN-α,the transcription of PKR, MxA and 2’-5’OAS were down-regulated in HepG2 cells expressing the core protein. In the presence of HCV core protein, ISRE-dependent luciferase activity also decreased. Further study indicated that the core protein could inhibit the tyrosine phosphorylation of STAT1, whereas the level of STAT1 expression was unchanged. Accordingly, SOCS3, the negative regulator of the Jak/STAT pathway, was induced by HCV core protein. These results suggests that HCV core protein may interfere with the expression of some interferon-induced antiviral genes by inhibiting STAT1 phosphorylation and induction of SOCS3.