Impaired clearance of virus-infected hepatocytes in transgenic mice expressing the hepatitis C virus polyprotein.
OBJECTIVE
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.
Disson
Olivier
O
Institut de Génétique Moléculaire, Centre National Recherche Scientifique, Unite Mixte de Recherche 5535, IFR 122, Montpelier, France.
Haouzi
Delphine
D
Desagher
Solange
S
Loesch
Kim
K
Hahne
Michael
M
Kremer
Eric J
EJ
Jacquet
Chantal
C
Lemon
Stanley M
SM
Hibner
Urszula
U
Lerat
Hervé
H
D000257:Adenoviridae Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D000818:Animals; D000917:Antibody Formation; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D015870:Gene Expression; D016174:Hepacivirus / Q000378:metabolism*; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D020815:Polyproteins / Q000235:genetics / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019076:Transgenes; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism
D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D002352:Carrier Proteins; D020815:Polyproteins; D014764:Viral Proteins; D019014:fas Receptor