Hepatitis C virus (HCV) is a serious global health problem with an estimate of 170 million carriers worldwide. Most individuals exposed to this blood-borne pathogen develop chronic infection, which may result in severe liver complications as well as end-stage liver diseases including cirrhosis and hepatocellular carcinoma. Current treatment options are suboptimal with no effective vaccines available to date. Development of a readily accessible mouse model that is permissive to natural HCV infection is important to facilitate drug and vaccine discovery, and also to better understand the viral pathogenesis. The inherent difficulty is that HCV displays very limited tropism, infecting only livers from humans or chimpanzees. An attempt was made to elucidate the key determinants in rendering the murine intracellular environment permissive to HCV replication. The results revealed that deletion of the interferon regulatory factor-3 and overexpression of microRNA-122 can independently enhance viral subgenomic replication in murine fibroblasts, with microRNA-122 being the stronger determinant. Interestingly, the phenotype established by these genetic manipulations was insufficient to support full-length HCV genome replication. Murine hepatic cell lines, with or without microRNA-122 expression, were also non-permissive to genomic HCV replication, despite the fact that translation of viral RNA was observed. These results suggest that additional host-specific factor(s) are required to support replication of full-length HCV RNA. These studies provide insight on the essential factors capable of influencing permissiveness of rodent cells to HCV replication, and also suggest genetic modifications to be considered when modeling the complete viral life cycle in a rodent animal model.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:NSHD.ca#10222/13159 |
| Date | 09 December 2010 |
| Creators | Lin, Liang-Tzung |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
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