Basic-liver, pancreas, and biliary tractImpaired clearance of virus-infected hepatocytes in transgenic mice expressing the hepatitis C virus polyprotein☆
Section snippets
Materials and methods
Antibodies anti-murine Fas (Jo2 clone) and anti-cytochrome C (6H2-B4 clone) were from PharMingen (San Diego, CA), the polyclonal anti-caspase 3 was from Cell Signaling Technology (Beverly, MA), and the polyclonal anti-caspase 8 antibody was from Chemicon (Temecula, CA). Goat anti-Bid was from R&D Systems (Abingdon, UK) or a gift from Jean-Claude Martinou (Université de Genève, Switzerland). Polyclonal anti-GAPDH (glyceraldehydes-3-phosphate dehydrogenase) antibody was a gift from Jean-Marie
HCV gene expression protects hepatocytes from cytotoxic immune response
FL-N/35 transgenic mice express the entire polyprotein of HCV under control of the murine albumin promoter/enhancer within a C57/BL6 genetic background (Figure 1A). The level of expression is very low, requiring the use of reverse-transcriptase (RT)-PCR to detect transgenic RNA transcripts, but it is nonetheless associated with the development of hepatic steatosis and hepatocellular carcinoma in male animals.11 Thus, both the abundance of viral proteins and the phenotypic features of these
Discussion
The mechanisms by which HCV evades the immune system to establish and maintain a persistent infection in most human hosts remain poorly understood.4
It is likely that multiple mechanisms contribute to viral persistence. Strong in vitro evidence supports the disruption of both interferon signaling pathways and effector functions by the viral proteins NS3/4A and NS5A.6, 8 However, global mRNA profiling of HCV-infected chimpanzees suggests that type 1 interferon genes are nonetheless strongly
Acknowledgements
We are grateful to Dr. Jean-Claude Martinou and Sylvie Montessuit for the gift of recombinant murine Bid and 224A anti-Bid antibody, Dr. Antonio Freitas for the fluorochrome-conjugated anti-CD3, anti-CD4 and anti-CD8 antibodies. We thank Eric Joffre for expert assistance with animal experiments, Dr. Jean-François Emile for help with histological analyses, Audrey Ceschia for help with quantification of apoptosis, and Francis Bodola for quantitation of adenovirus DNA in liver tissues. We are
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2017, European Journal of PharmacologyHepatitis C virus induces a prediabetic state by directly impairing hepatic glucose metabolism in mice
2017, Journal of Biological ChemistryHepatitis C viral proteins perturb metabolic liver zonation
2015, Journal of HepatologyCitation Excerpt :Transgenic mice with liver-targeted expression of the HCV full-length open reading frame (FL-N/35 lineage) develop a spectrum of liver metabolic disorders, including alterations of lipid metabolism [7] and micro- and macro-vesicular steatosis [8]. In addition to reproducing a wide range of pathological features associated with chronic hepatitis C [9,10], males of this lineage are cancer-prone [8]. While this phenotype is perfectly reproducible in different animal colonies [11], some genetic backgrounds, for example the widely used CB57Bl/6 animals, are protected from the HCV viral protein-driven carcinogenesis ([12] and our unpublished data).
Hepatitis C
2014, Mandell, Douglas, and Bennett's Principles and Practice of Infectious DiseasesHepatitis C virus (HCV) protein expression enhances hepatic fibrosis in HCV transgenic mice exposed to a fibrogenic agent
2012, Journal of HepatologyCitation Excerpt :They were used in conformation with the European Community Council directive. Animals were bred and housed as previously described [2]. Studies were performed on age-matched 7- to 10-month-old males.
Hepatitis C virus proteins induce lipogenesis and defective triglyceride secretion in transgenic mice
2009, Journal of Biological ChemistryCitation Excerpt :The precise role of HCV protein expression in these phenomena is unclear. The transgenic mice used here, which expresses the HCV full-length open reading frame, are a particularly relevant model for studying HCV protein-induced abnormalities, because all of the HCV proteins are produced at the same time at physiologically relevant levels, without infectious virus production (16, 26–28). We have previously reported that two lineages of transgenic mice expressing the HCV full-length open reading frame develop more frequent and more severe hepatocellular steatosis than their nontransgenic littermates (16).
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Supported by INSERM, CNRS, ANRS, the French Ministry of Research “Programme de Recherche Fondamentale en Microbiologie, Maladies Infectieuses et Parasitaires” (UH), and the National Institute of Allergy and Infectious Diseases through the Hepatitis C Cooperative Research Center U19-AI40035 (S.L.). Dr. Lerat was a recipient of fellowships from Ligue Nationale contre le Cancer and ANRS.