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Dissertation zugänglich unter
URN: urn:nbn:de:gbv:18-61148
URL: http://ediss.sub.uni-hamburg.de/volltexte/2013/6114/


Humanized chimeric uPA mouse model for the study of Hepatitis B and D virus interactions and preclinical drug evaluation

Über die Etablierung eines für das Hepatitis-Delta-Virus geeigneten uPA Mausmodells mit humanen Hepatozyten zur Erforschung von Interaktionen zwischen dem Hepatitis-B- und D-Virus sowie präklinische Medikamentenevaluation

Mancke, Lida Victoria

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 Dokument 1.pdf (1.203 KB) 


SWD-Schlagwörter: Hepatitis-D-Virus , Hepatitis-B-Virus
Basisklassifikation: 44.61
Institut: Medizin
DDC-Sachgruppe: Medizin, Gesundheit
Dokumentart: Dissertation
Hauptberichter: Dandri, Maura (PD Dr.)
Sprache: Mehrsprachig
Tag der mündlichen Prüfung: 29.01.2013
Erstellungsjahr: 2012
Publikationsdatum: 27.03.2013
Kurzfassung auf Englisch: No specific drugs are currently available against hepatitis delta virus (HDV), a defective virus leading to the most severe form of chronic viral hepatitis in man. The lack of convenient HDV infection models has hampered the development of effective therapeutics. In this study, naı¨ve and hepatitis B virus (HBV) chronically infected humanized uPA/SCID mice were employed to establish a small animal model of HBV/HDV coinfection and superinfection. For preclinical antiviral drug evaluation, the GMP version of the myristoylated
preS-peptide (Myrcludex-B), a lipopeptide derived from the pre-S1 domain of the HBV envelope, was applied to prevent de novo HBV/HDV coinfection in vivo. Virological parameters were determined at serological and intrahepatic level both by real-time polymerase chain reaction (PCR) and by immunohistochemistry. Establishment of HDV infection was highly efficient in both HBV-infected and naı¨ve chimeric mice with HDV titers rising up to 1 3 10E9 copies/mL. Notably, HDV superinfection led to a median 0.6log reduction of HBV viremia, which although not statistically significant suggests that HDV may hinder HBVreplication. In the setting of HBV/HDV simultaneous infection, a majority of human hepatocytes stained HDAg-positive long before HBV spreading was completed, confirming that HDV can replicate intrahepatically also in the absence of HBV infection. Furthermore, the increase of HBV viremia and intrahepatic cccDNA loads was significantly slower than in HBV mono-infected mice. Treatment with the HBV entry inhibitor
Myrcludex-B, efficiently hindered the establishment of HDV infection in vivo.
Conclusion: We established an efficient model of HBV/HDV infection to exploit mechanisms of viral interference in human hepatocytes and to test the efficacy of an HDV-entry inhibitor in vivo.

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