Specific and Nonhepatotoxic Degradation of Nuclear Hepatitis B Virus cccDNA

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

Edité par CCSD ; American Association for the Advancement of Science (AAAS) -

International audience. 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.

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