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Characterization of liver histopathology in a transgenic mouse model expressing genotype 1a hepatitis C virus core and envelope proteins 1 and 2

¹ Division of Virology, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON, Canada, K1H 8L1
² Department of Microbiology Immunology and Biochemistry, University of Ottawa, Ottawa, ON, Canada, K1N 6N5
³ Ottawa Health Research Institute, Molecular Medicine Program, Ottawa, ON, Canada, K1H 8L6
⁴ Department of Veterinary Pathology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, Canada, S7N 5B4
⁵ Department of Veterinary Microbiology, Veterinary Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK, Canada, S7N 5E3
⁶ Division of Blood Borne Pathogens, Health Canada, Ottawa, ON, Canada, K1A 0L2

Correspondence
Francisco Diaz-Mitoma
diaz{at}exchange.cheo.on.ca

Hepatitis C virus (HCV) is a major cause of chronic hepatitis and hepatocellular carcinoma worldwide. The purpose of this study was to determine how the HCV structural proteins affect the dynamic structural and functional properties of hepatocytes and measure the extra-hepatic manifestations induced by these viral proteins. A transgenic mouse model was established by expressing core, E1 and E2 proteins downstream of a CMV promoter. HCV RNA was detected using RT-PCR in transgenic mouse model tissues, such as liver, kidney, spleen and heart. Expression of the transgene was analysed by real-time PCR to quantify viral RNA in different tissues at different ages. Immunofluorescence analysis revealed the expression of core, E1 and E2 proteins predominantly in hepatocytes. Lower levels of protein expression were detected in spleen and kidneys. HCV RNA and viral protein expression increased in the liver with age. Histological analysis of liver cells demonstrated steatosis in transgenic mice older than 3 months, which was more progressed with age. Electron microscopy analysis revealed alterations in nuclei, mitochondria and endoplasmic reticulum. HCV structural proteins induce a severe hepatopathy in the transgenic mouse model. These mice became more prone to liver and lymphoid tumour development and hepatocellular carcinoma. In this model, the extra-hepatic effects of HCV, which included swelling of renal tubular cells, were mild. It is likely that the HCV structural proteins mediate some of the histological alterations in hepatocytes by interfering with lipid transport and liver metabolism.

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