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Hepatitis C virus (HCV) is a major cause of chronic liver disease worldwide. The severity of disease varies widely from mild illness to cirrhosis and hepatocellular carcinoma. The progression of liver fibrosis in HCV patients determines the prognosis and, thus, the need for and urgency of therapy. In addition to viral and environmental behavioral factors, host genetic diversity is believed to contribute to the spectrum of clinical outcomes of patients chronically infected with HCV. The sequencing of the human genome together with the development of high-throughput technologies has provided opportunities to distinguish discrete subsets of HCV disease and predict the disease outcome or the response to therapy. This article reviews genetic, genomic, and proteomic aspects associated with the natural history of HCV infection (i.e., viral clearance, fibrosis progression) and the response to therapy.
Hepatitis C virus (HCV) is a major cause of chronic liver disease with ~170 million people infected across the globe. HCV is an enveloped avivirus with a 9.6-kb single-strand RNA genome, which was identified in 1989. The HCV RNA genome serves as template for replication of the virus and as viral messenger RNA for production of the virus. It is translated into a polyprotein, which is cleaved by proteases. HCV enzymes (i.e., NS2 3 and NS3 4A proteases, NS3 helicase, and NS5B RdRp) are essential for HCV replication and, therefore, represent potential drug discovery targets.
Until recently, the absence of a cell culture model supporting full replication of HCV and the convenience of animal models has limited knowledge of the HCV life cycle and the development of and testing for antiviral molecules. Chimpanzee is the only animal model for HCV infection. The development of a subgenomic HCV RNA replicon capable of replication in the human hepatoma cell line Huh7 has been a significant advance. Recently, complete replication of HCV in cell culture has been achieved.
Persistent infections with HCV are likely to depend on inhibition of host defenses by the virus. It is suggested that interferon (IFN)-α/β-inducible genes are expressed during HCV infection by direct activation of interferon regulatory factor-3 (IRF-3,) nuclear factor NFkB1, or JUN through IFN-independent signaling events and during chronic HCV infection through IFN-dependent signaling events in host cells. In the latter case, endogenous IFN-α/β bind to a common receptor expressed at the surface of target cells. Receptor engagement leads to the activation of STAT1 and STAT2 (but not STAT3), which, together with ISGF3G/IRF9, bind to cis-acting IFN-stimulated response elements (ISREs), thereby activating the transcription of IFN-α/β-inducible genes. It has been shown that the HCV NS3 4A serine protease blocks the phosphorylation and effector action of IRF-3 as a key cellular antiviral signaling molecule. Disruption of HCV NS3 4A protease function by mutation or by a ketoamide peptidomimetic inhibitor relieved this blockage and restored IRF-3 phosphorylation after cellular challenge with an unrelated virus. Furthermore, dominant-negative or constitutively active IRF-3 mutants, respectively, enhanced or suppressed HCV replication. Thus, the NS3 4A protease represents a dual therapeutic target, the inhibition of which may block viral replication and restore IRF-3 control of HCV infection.
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