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Published Online February 20 2014
Science DOI: 10.1126/science.1243462
Research Article
Specific and Nonhepatotoxic Degradation of Nuclear Hepatitis B Virus cccDNA
Julie Lucifora1,2,*,
Yuchen Xia1,*,
Florian Reisinger1,
Ke Zhang1,
Daniela Stadler1,
Xiaoming Cheng1,
Martin F. Sprinzl1,3,
Herwig Koppensteiner1,
Zuzanna Makowska4,
Tassilo Volz5,
Caroline Remouchamps6,
Wen-Min Chou1,
Wolfgang E. Thasler7,
Norbert Hüser8,
David Durantel9,
T. Jake Liang10,
Carsten Münk11,
Markus H. Heim4,
Jeffrey L. Browning12,
Emmanuel Dejardin6,
Maura Dandri2,5,
Michael Schindler1,
Mathias Heikenwalder1,†‡,
Ulrike Protzer1,2,†‡
+ Author Affiliations
1Institute of Virology, Technische Universität München–Helmholtz Zentrum München, 81675 Munich, Germany.
2German Center for Infection Research (DZIF), Munich and Hamburg sites, Germany.
31st Medical Department, University Hospital Mainz, 55131 Mainz, Germany.
4Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland.
5Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
6GIGA-Research Laboratory of Molecular Immunology and Signal Transduction, University of Liège, 4000 Liège, Belgium.
7Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Grosshadern Hospital, Ludwig Maximilians University, 81377 Munich, Germany.
8Department of Surgery, University Hospital Rechts der Isar, Technische Universität München, 85748 Munich, Germany.
9INSERM U1052, CNRS UMR 5286, Cancer Research Center of Lyon, University of Lyon, LabEx DEVweCAN, 69007 Lyon, France.
10Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA.
11Clinic for Gastroenterology, Hepatology and Infectiology, Medical Faculty, Heinrich-Heine University, 40225 Düsseldorf, Germany.
12Department of Immunobiology, Biogen Idec, Cambridge, MA 02142, USA.
↵†Corresponding author. E-mail: [email protected] (U.P.); [email protected] (M.H.)
↵* These authors contributed equally to this work.
↵‡ These authors contributed equally to this work.
Abstract
Current antivirals can control but not eliminate hepatitis-B-virus (HBV), because HBV establishes a stable nuclear cccDNA. Interferon-α treatment can clear HBV but is limited by systemic side effects. Here, 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 3B 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 - e.g., by lymphotoxin-β-receptor activation - allows development of new therapeutics that combined with existing antivirals may cure hepatitis B.
Received for publication 18 July 2013.
Accepted for publication 5 February 2014.
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