Specific and Nonhepatotoxic Degradation of Nuclear Hepatitis B Virus cccDNA

作者：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 Hüser, David Durantel, T. Jake Liang, Carsten Münk, Markus H. Heim, Jeffrey L. Browning, Emmanuel Dejardin, Maura Dandri, Michael Schindler, Mathias Heikenwälder, Ulrike Protzer · 发表于：Science · 年份：2014 · DOI：10.1126/science.1243462 · 被引用次数：891 · 研究领域：Hepatitis B Virus Studies、Immunotherapy and Immune Responses、HIV Research and Treatment

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.