New Insights into Structure and Replication of the Hepatitis C Virus and Clinical Implications

Abstract

With the advent of efficient systems to propagate the hepatitis C virus (HCV) in cultured cells important new discoveries have been made. For instance, several molecules required for HCV infection of hepatocytes have been identified and first insights into the entry pathway have been gained. Ribonucleic acid (RNA) replication and virion assembly were found to be tightly linked to lipid metabolism and numerous host factors contributing to viral replication have been identified. Some of them such as cyclophilin A or microRNA-122 are attractive targets for antiviral therapy as are the viral serine-type protease residing in nonstructural protein 3 (NS3) and the NS5B RNA-dependent RNA polymerase. More recently, the viral phosphoprotein NS5A emerged as an additional and very promising target for selective therapy. These results illustrate the great progress that has been made in the HCV field and how this knowledge can be used to devise innovative strategies to counteract this pathogen.

Hepatitis C Virus-Induced Cancer Stem Cell-Like Signatures in Cell Culture and Murine Tumor Xenografts

“…The protein is also considered a marker for aggressive HCC subtypes. Furthermore, the overexpression of CK19 in HCC correlates with the lower rates of patient survival and higher rates of tumor recurrence (40,41). These observations led us to investigate CK19 levels in the cultured cells.…”

“…The HCV genome (9,600 nucleotides [nt]) encodes a single polyprotein that is processed cotranslationally into three structural (C, E1, and E2) and seven nonstructural (NS) polypeptides (p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B) (25). Similar to other positive-strand RNA viruses, HCV replicates via synthesis of negative-strand RNA using replication complexes (RCs) comprising most of the NS proteins and as-yet-undefined cellular factors (5,41). During infection, HCV induces weblike membranous structures and uses lipid raft and microtubule filaments (MTFs) for its replication and transport (19,35,54).…”

TCR-Redirected Human T Cells Inhibit Hepatitis C Virus Replication: Hepatotoxic Potential Is Linked to Antigen Specificity and Functional Avidity

“…HCV NS5A and NS3 are essential components of the viral replicase complex and are constantly present in the HCV-replicating cells because their enzymatic activities are required in the life cycle of the HCV (33). We aimed at targeting HCV NS5A and NS3 protein-positive hepatocytes to eliminate residual HCV-replicating cells by inducing a pre-engineered cytotoxic T cell response mediated by Ag-specific TCRs.…”

Expression of the Novel Hepatitis C Virus Core+1/ARF Protein in the Context of JFH1-Based Replicons

“…The single-stranded positive-sense RNA genome of HCV (9.6 kb) encodes a polyprotein precursor of about 3,000 amino acids flanked by conserved untranslated regions (UTRs) (4,5). The UTRs are required for RNA translation and replication, and an internal ribosome entry site (IRES) within the 5= UTR controls translation initiation (6).…”