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.

journal_name

Gastroenterology

journal_title

Gastroenterology

authors

Disson O,Haouzi D,Desagher S,Loesch K,Hahne M,Kremer EJ,Jacquet C,Lemon SM,Hibner U,Lerat H

doi

10.1053/j.gastro.2003.12.005

keywords:

subject

Has Abstract

pub_date

2004-03-01 00:00:00

pages

859-72

issue

3

eissn

0016-5085

issn

1528-0012

pii

S0016508503020183

journal_volume

126

pub_type

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