Identification of host factors required for HCV-IRES activity and their physiological roles in liver disease

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Background and aim : Translation of the hepatitis C virus (HCV) is mediated by an internal ribosome entry site (IRES). Many translation initiation factors interact with HCV IRES; however, the functional relevance of these factors for the translation and replication of HCV has not been clarified. Methods : Two different subgenomic HCV replicons, NNeo/3-5B and MH14C, were used. NNeo/3-5B consists of an HCV replicon with a standard structure in which NS3-NS5 was translated by encephalomyocarditis (EMCV) IRES. MH14C is an HCV replicon with a modified structure in which EMCV IRES was replaced with HCV IRES. Of 14 translation initiation factors suppressed by antisense oligodeoxynucleotides or siRNA, La protein, PTB, eIF3 p170, eIF2 gamma, and PSMA 7 affected HCV IRES activity and the replication of MH14C. However, these factors did not affect EMCV IRES activity and the replication of NNeo/3-5B. La protein, eIF2 gamma, and PSMA7 were significantly correlated with HCV RNA in the liver of 37 patients with chronic hepatitis C (CH-C). Gene expression profiling using a cDNA microarray revealed these initiation factors were induced in CH-C and clustered in a group of genes representing inflammation, DNA repair and stress responses. One of the HCV coding proteins, NS5A, activated the La protein promoter and the interferon sensitivity-determining region in NS5A was responsible for the activation. Conclusions: HCV replication was highly dependent on translation initiation factors that were induced in tissue lesions of CH-C. The induction of La protein by the HCV protein NS5A might support the replication and persistent infection of HCV.