Hepatitis C virus (HCV) causes persistent infection inhepatocytes, and this infection is, in turn, strongly associated with the development of hepatocellular carcinoma. To clarify the mechanisms underlying these effects, we established a Cre/loxP conditional expression system for the precisely self-trimmed HCV genome in human liver cells. Passage of hepatocytes expressing replicable full-length HCV (HCR6-Rz) RNA caused upregulation of anchorage-independent growth after 44 days. In contrast, hepatocytes expressing HCV structural, nonstructural, or all viral proteins showed no significant changes after passage for 44 days. Only cells expressing HCR6-Rz passaged for 44 days displayed acceleration of CDK activity, hyperphosphorylation of Rb, and E2F activation. These results demonstrate that full genome HCV expression up-regulates the CDK-Rb-E2F pathway much more effectively than HCV proteins during passage.Hepatitis C virus (HCV) 1 causes the persistent infection chronic hepatitis in most infected patients. This disorder eventually progresses to cirrhosis and hepatocellular carcinoma (HCC). Numerous studies have provided evidence supporting a link between chronic HCV infection and HCC (1, 2). However, exactly how HCV infection could be directly involved in the development of HCC remains unclear because of the lack of an efficient in vitro infection system.HCV is a member of the Flaviviridae family and has a positive-strand RNA genome (ϳ9.6 kb). Viral proteins are synthesized as a single polyprotein, which is then cleaved into structural (core, E1, and E2) and nonstructural (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) proteins. In vitro expression of HCV core protein reportedly influences cell growth regulation, and the protein can interact with the cytoplasmic tail of a lymphotoxin- receptor (3), the death domain of tumor necrosis factor receptor-1 (4), and NF-B (5), resulting in enhancement or inhibition of Fas-and tumor necrosis factor-␣-mediated apoptosis. HCV structural protein inhibits Fas-mediated apoptosis by inhibiting cytochrome c release from mitochondria in mice (6). Cellular transformation has been shown to be caused by HCV core protein in the presence of the ras gene (7,8) and by loss of function of LZIP (9) and the presence of STAT3 (signal transducer and activator of transcription-3) (10). NS3 (11) and NS4B (12) proteins reportedly display tumorigenicity in the presence of ras. These results indicate that expression of individual HCV proteins does not cause cellular transformation in vitro. HCV core protein transgenic mice reportedly show induced steatosis and, after 16 months of age, develop HCC (13). In contrast, HCV structural protein transgenic mice do not display neoplastic or cancerous lesions in the liver by 20 months of age (14). Moreover, conditional expression of an HCV structural protein region (nucleotides 294 -3435) causes hepatic injury in transgenic mice (15), but HCC is not observed by at least 16 months of age (data not shown). The frequency of HCC occurrence is reportedly higher in full-...
Most acute hepatitis C virus (HCV) infections become chronic and some progress to liver cirrhosis or hepatocellular carcinoma. Standard therapy involves an interferon (IFN)-α-based regimen, and efficacy of therapy has been significantly improved by the development of protease inhibitors. However, several issues remain concerning the injectable form and the side effects of IFN. Here, we report an orally available, small-molecule type I IFN receptor agonist that directly transduces the IFN signal cascade and stimulates antiviral gene expression. Like type I IFN, the small-molecule compound induces IFN-stimulated gene (ISG) expression for antiviral activity in vitro and in vivo in mice, and the ISG induction mechanism is attributed to a direct interaction between the compound and IFN-α receptor 2, a key molecule of IFN-signaling on the cell surface. Our study highlights the importance of an orally active IFN-like agent, both as a therapy for antiviral infections and as a potential IFN substitute.
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