Mechanisms of interferon action and resistance in chronic hepatitis C virus infection: Lessons learned from cell culture studies

Abstract

Alpha interferon, usually in combination with ribavirin, is currently the standard care for patients infected with hepatitis C virus. Unfortunately, a significant number of patients fail to eradicate their infection with this regimen. The molecular details concerning the failure of many patients to achieve sustained clearance of the virus infection after interferon therapy are currently unknown. The primary focus of this chapter is to provide an overview of interferon action and resistance against hepatitis C virus (HCV) based on our understanding developed from in vitro experiments. Interferon first binds to receptors on the cell surface; this initiates a cascade of signal transduction pathways leading to the activation of antiviral genes. Using a cell culture model, we determined that the activation of an interferon promoter (interferon inducible genes) is important for a successful antiviral response against HCV. The level of activation of the IFN promoter by exogenous interferon appears to vary among different replicon cell lines. It was observed that a replicon cell line showing low activation of the IFN promoter frequently develops resistant phenotypes compared to cell lines with higher activation. Furthermore, interferon-alpha, -beta, and -gamma are each found to inhibit replication of HCV in the cell culture. The antiviral action of interferon is targeted to the highly conserved 5' untranslated region (5' UTR) utilized by the virus to translate protein by an internal ribosome entry site (IRES) mechanism. This effect is the same among HCVs of other genotypes. Interferon inhibits translation of HCV by blocking at the level of formation of polyribosomes on the IRES containing mRNA. These in vitro studies suggest that differences in the regulation of IRES-mediated translation by interferon among hepatic cell clones may be directly related to the development of interferon resistance in chronic HCV infection. © 2008 Springer Science+Business Media, LLC.