Abstract
360 million people are chronically infected with the human hepatitis B virus (HBV) and are consequently prone to develop liver cirrhosis and hepatocellular carcinoma1. As approved therapeutic regimens—which modulate patients' antiviral defenses or inhibit the viral reverse transcriptase—are generally noncurative, strategies interfering with other HBV replication steps are required. Expanding on our demonstration that acylated peptides derived from the large HBV envelope protein block virus entry in vitro2,3,4,5, we show their applicability to prevent HBV or woolly monkey hepatitis B virus infection in vivo, using immunodeficient urokinase-type plasminogen activator (uPA) mice repopulated with primary human or Tupaia belangeri hepatocytes6,7. Accumulation of the peptides in the liver, their extraordinary inhibitory potency and specific mode of action permit subcutaneous delivery at very low doses. Inhibition of hepadnavirus entry thus constitutes a therapeutic approach to prevent primary HBV infection, such as after liver transplantation, and might also restrain virus spread in chronically infected patients.
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Acknowledgements
We thank P. Gripon and J. Taylor for many helpful discussions, R. Bartenschlager for continuous support and critical reading of the manuscript, R. Reusch, N. Jaeger and H. Eskerski for excellent animal care and C. Kuhn for help with the cryosections. This work was supported by the German Competence Network for Viral Hepatitis (Hep-Net), funded by the German Ministry of Education and Research (BMBF), grant no. 01 KI 0418. S.U. and J.P. were supported by the Deutsche Forschungsgemeinschaft (DFG), grant no. UR72/1-3, UR72/1-4 and Pe608/2-5. J.P. was also supported by the European Union Vigilance Network for the management of antiviral drug resistance (Virgil).
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J.P. and M.D. designed research, analyzed data and wrote the manuscript; W.M. and U.H. synthesized and labeled peptides and performed biodistribution experiments; M.L. performed transplantation experiments and immunohistochemistry; T.V. performed transplantation experiments and molecular assays; F.v.W. provided Tupaia belangeri hepatocytes; L.F. and J.-M.P. provided human hepatocytes; B.E. performed in situ biodistribution experiments; S.S. purified HBV virus stocks and analyzed data; S.U. initiated and designed research, analyzed data and wrote the manuscript.
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Petersen, J., Dandri, M., Mier, W. et al. Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein. Nat Biotechnol 26, 335–341 (2008). https://doi.org/10.1038/nbt1389
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DOI: https://doi.org/10.1038/nbt1389
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