Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA

Julie Lucifora, Yuchen Xia, Florian Reisinger, Ke Zhang, Daniela Stadler, Xiaoming Cheng, Martin F. Sprinzl, Herwig Koppensteiner, Zuzanna Makowska, Tassilo Volz, Caroline Remouchamps, Wen Min Chou, Wolfgang E. Thasler, Norbert Hus̈er, David Durantel, T. Jake Liang, Carsten Mun̈k, Markus H. Heim, Jeffrey L. Browning, Emmanuel DejardinMaura Dandri, Michael Schindler, Mathias Heikenwalder, Ulrike Protzer

Research output: Contribution to journalArticlepeer-review

Abstract

Current antiviral agents can control but not eliminate hepatitis B virus (HBV), because HBV establishes a stable nuclear covalently closed circular DNA (cccDNA). Interferon-α treatment can clear HBV but is limited by systemic side effects. We describe how interferon-α can induce specific degradation of the nuclear viral DNA without hepatotoxicity and propose lymphotoxin-β receptor activation as a therapeutic alternative. Interferon-α and lymphotoxin-β receptor activation up-regulated APOBEC3A and APOBEC3B cytidine deaminases, respectively, in HBV-infected cells, primary hepatocytes, and human liver needle biopsies. HBV core protein mediated the interaction with nuclear cccDNA, resulting in cytidine deamination, apurinic/apyrimidinic site formation, and finally cccDNA degradation that prevented HBV reactivation. Genomic DNA was not affected. Thus, inducing nuclear deaminases - for example, by lymphotoxin-β receptor activation - allows the development of new therapeutics that, in combination with existing antivirals, may cure hepatitis B.

Original languageEnglish (US)
Pages (from-to)1221-1228
Number of pages8
JournalScience
Volume343
Issue number6176
DOIs
StatePublished - 2014
Externally publishedYes

ASJC Scopus subject areas

  • General
  • History and Philosophy of Science

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