Page 125 - ebook HCC

PROGRAMME
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122 PROGRAMME AND ABSTRACTSAND ABSTRACTS GENEVA, SWITZERLAND EASL HCC SUMMIT 123
FEBRUARY 13 - 16, 2014

Poster Board Number B20

INVESTIGATING HEPATITIS C NOTES
VIRUS-ASSOCIATED PATHOGENESIS AND
CARCINOGENESIS IN AN IMMUNOCOMPETENT
SMALL ANIMAL MODEL

Daniel Rupp , Beate Straub , Mauricio Berriel Diaz , Thomas Longerich ,
2
2
3
1
Florian Heinzmann , Rahel Klein , Lars Zender , Dirk Grimm , Stephan Herzig ,
6
3
5
1
4
Volker Lohmann , Ralf Bartenschlager 1
1
2
1 Department for Infectious Diseases, Institute of Pathology, University of Heidelberg,
3 German Cancer Research Center, Heidelberg, Chronic Infections and Cancer,
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5
Helmholtz Centre for Infection Research, Braunschweig, University of Tübingen,
Tübingen, Bioquant, University of Heidelberg, Heidelberg, Germany
6
Corresponding author’s e-mail: drupp1984@yahoo.de
Introduction: Chronic hepatitis C virus (HCV) infection still is a major health burden
affecting 130 to 170 million people world wide, which are at high risk to develop liver cirrhosis
and hepatocellular carcinoma (HCC). Thus far, there is no immunocompetent small animal
model allowing investigation of HCV-associated pathogenesis and carcinogenesis.
BASIC POSTER ABSTRACTS characterization of viral and host determinants that are involved in key processes of HCV- BASIC POSTER ABSTRACTS
Aims: In this study we aim to establish an immunocompetent small animal model allowing
associated pathogenesis and carcinogenesis.
Methodology: Expression cassettes encoding for various HCV proteins that are derived
from different genotypes are constructed and analyzed for pathogenetic properties in
vivo. In a first proof of principle study constructs based on the pCAGGS-vector encoding
HCV core derived from genotype 2 and genotype 3 were delivered into the liver via
hydrodynamic tail vein injection. This vector allows integration into the host genome via
transposable elements and thus, long term expression of the viral gene.
Results: Although histopathological investigation revealed steatosis in one out of four mice
inoculated with the genotype 3-containing core construct 5 to 12 months after injection,
fibrosis, cirrhosis or tumor formation was not observed in these animals. Results obtained
by Western blot and PCR suggest that this is most likely due to very low frequency of cells
supporting long-term expression of the viral protein.
Conclusions: To overcome this limitation, we currently elucidate HCV expression in mice
by using vectors based on adeno-associated viruses (AAV). Their delivery is much less
stressful for the cardiovascular system, as compared to hydrodynamic tail vein injection.
Importantly, highly efficient liver-specific gene delivery and expression is mediated via
capsid proteins derived from AAV8 and a liver-specific promoter, respectively. Currently
we are elucidating possibilities offered by a flexible AAV-based transduction system to
investigate HCV-associated mechanisms contributing to pathogenesis and carcinogenesis
in a genotype-specific manner.