Impaired clearance of virus-infected hepatocytes in transgenic mice expressing the hepatitis C virus polyprotein

Abstract : Background & Aims: Multiple molecular mechanisms are likely to contribute to the establishment of persistent infection by hepatitis C virus (HCV). The aim of this work was to study the evasion of cell-mediated antiviral immune responses in transgenic mice with liver-targeted expression of the hepatitis C viral genome. These mice develop steatosis and hepatocellular carcinoma and constitute a murine model of chronic HCV infection. Methods: Mice of the FL-N/35 lineage were infected with replication-deficient adenoviral vectors encoding beta-galactosidase, and the persistence of infected cells was measured by histochemistry and enzymatic assays. Results: Hepatocytes from the HCV+ transgenic mice are deficient in eliminating an adenoviral infection, despite an apparently normal T-cell response. The defect in adenoviral clearance was associated with resistance of transgenic hepatocytes to apoptosis induced by Fas/ APO1/CD95 death receptor stimulation, a major pathway of cell killing by cytotoxic T lymphocytes. The attenuation of Fas-mediated apoptosis observed in the murine model was associated with a reduced abundance of Bid, a BH3-only member of the Bcl-2 family of apoptosis regulators. Conclusions: Our results suggest that viral evasion of cell-mediated immune responses leading to apoptotic death of hepatocytes may contribute to viral persistence. Such a mechanism might also contribute to the development of liver cancer in HCV.
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Submitted on : Friday, August 2, 2019 - 2:22:05 PM
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O. Disson, D. Haouzi, S. Desagher, K. Loesch, M. Hahne, et al.. Impaired clearance of virus-infected hepatocytes in transgenic mice expressing the hepatitis C virus polyprotein. Gastroenterology, 2004, 126 (3), pp.859--872. ⟨hal-02262405⟩

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