Humanized chimeric uPA mouse model for the study of hepatitis B and D virus interactions and preclinical drug evaluation.
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Humanized chimeric uPA mouse model for the study of hepatitis B and D virus interactions and preclinical drug evaluation. / Lütgehetmann, Marc; Mancke, Lisa; Volz, Tassilo; Helbig, Martina; Allweiss, Lena; Bornscheuer, Till; Pollok, Jörg-Matthias; Lohse, Ansgar W.; Petersen, J; Urban, Stephan; Dandri-Petersen, Maura.
In: HEPATOLOGY, Vol. 55, No. 3, 3, 2012, p. 685-694.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Humanized chimeric uPA mouse model for the study of hepatitis B and D virus interactions and preclinical drug evaluation.
AU - Lütgehetmann, Marc
AU - Mancke, Lisa
AU - Volz, Tassilo
AU - Helbig, Martina
AU - Allweiss, Lena
AU - Bornscheuer, Till
AU - Pollok, Jörg-Matthias
AU - Lohse, Ansgar W.
AU - Petersen, J
AU - Urban, Stephan
AU - Dandri-Petersen, Maura
PY - 2012
Y1 - 2012
N2 - 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, naïve 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 naïve chimeric mice with HDV titers rising up to 1 × 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 HBV replication. 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.
AB - 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, naïve 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 naïve chimeric mice with HDV titers rising up to 1 × 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 HBV replication. 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.
KW - Animals
KW - Comorbidity
KW - Humans
KW - Treatment Outcome
KW - Cells, Cultured
KW - Disease Models, Animal
KW - Mice
KW - Mice, Transgenic
KW - Mice, SCID
KW - Virus Replication/drug effects
KW - Urokinase-Type Plasminogen Activator/genetics
KW - Antiviral Agents/pharmacology/therapeutic use
KW - Chimera/virology
KW - Coinfection/drug therapy
KW - Hepatitis B/drug therapy/epidemiology
KW - Hepatitis B virus/physiology
KW - Hepatitis D/drug therapy/epidemiology
KW - Hepatitis Delta Virus/physiology
KW - Hepatitis delta Antigens/metabolism
KW - Hepatocytes/pathology/virology
KW - Lipopeptides/pharmacology/therapeutic use
KW - Animals
KW - Comorbidity
KW - Humans
KW - Treatment Outcome
KW - Cells, Cultured
KW - Disease Models, Animal
KW - Mice
KW - Mice, Transgenic
KW - Mice, SCID
KW - Virus Replication/drug effects
KW - Urokinase-Type Plasminogen Activator/genetics
KW - Antiviral Agents/pharmacology/therapeutic use
KW - Chimera/virology
KW - Coinfection/drug therapy
KW - Hepatitis B/drug therapy/epidemiology
KW - Hepatitis B virus/physiology
KW - Hepatitis D/drug therapy/epidemiology
KW - Hepatitis Delta Virus/physiology
KW - Hepatitis delta Antigens/metabolism
KW - Hepatocytes/pathology/virology
KW - Lipopeptides/pharmacology/therapeutic use
M3 - SCORING: Journal article
VL - 55
SP - 685
EP - 694
JO - HEPATOLOGY
JF - HEPATOLOGY
SN - 0270-9139
IS - 3
M1 - 3
ER -
