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Journal of Hepatology
Volume 58, Issue 5, May 2013, Pages 861–867
The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus
Tassilo Volz1, †,
Lena Allweiss1, †,
Mounira Ben M´Barek1,
Michael Warlich1,
Ansgar W. Lohse1,
Jörg M. Pollok2,
Alexander Alexandrov3,
Stephan Urban4,
Jörg Petersen5,
Marc Lütgehetmann1, 6, ††,
Maura Dandri1, Corresponding author contact information, ††, E-mail the corresponding author
1 Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
2 Department of Hepatobiliary Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
3 MYR-GMBH, Bad Homburg, Germany
4 Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Germany
5 IFI Institute for Interdisciplinary Medicine at Asklepios Clinic St. Georg, Hamburg, Germany
6 Department of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
http://dx.doi.org/10.1016/j.jhep.2012.12.008, How to Cite or Link Using DOI
Background & Aims
Currently approved antivirals rarely cure hepatitis B virus (HBV) infection. Therefore additional therapeutic strategies interfering with other viral replication steps are needed. Using synthetic lipopeptides derived from the HBV envelope protein, we previously demonstrated prevention of de novo HBV infection in vivo. We aimed at investigating the ability of the lipopeptide Myrcludex-B to block HBV spreading post-infection.
Methods
uPA/SCID mice reconstituted with human hepatocytes were infected with HBV. Daily subcutaneous Myrcludex-B administration was initiated either 3 days, 3 weeks or 8 weeks post HBV inoculation. Viral loads were quantitated in serum and liver, and visualized by immunohistochemistry.
Results
Myrcludex-B efficiently prevented viral spreading from the initially infected human hepatocytes, as demonstrated by the lack of increase in viremia, antigen levels and amount of HBcAg-positive human hepatocytes determined 6 weeks after treatment. Myrcludex-B efficiently blocked HBV dissemination also when treatment was started in the ramp-up phase of infection, in mice displaying moderate levels of circulating virions (median 3 × 106 HBV DNA copies/ml). Notably, after 6 weeks of treatment, not only the amount of HBcAg-positive hepatocytes, but also intrahepatic cccDNA loads, remained comparable to values found in mice sacrificed 3 weeks post-infection. In none of the experimental settings, drug administration affected human hepatocyte half-life or altered virion productivity.
Conclusions
Myrcludex-B efficiently not only prevented HBV spreading from infected human hepatocytes in vivo, but also hindered amplification of the cccDNA pool in initially infected hepatocytes. Administration of an entry inhibitor, possibly used in combination with current HBV drugs, may improve patients’ treatment outcome.
Abbreviations
IFN, interferon;
HBV, hepatitis B virus;
pgRNA, pregenomic RNA;
cccDNA, covalently closed circular DNA;
rcDNA, relaxed circular DNA
Keywords
HBV;
uPA;
Humanized mice;
Entry inhibitor;
cccDNA
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发表于 2013-5-5 18:12
