title: Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA.
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.
authors.affiliation: Institute of Virology, Technische Universität München-Helmholtz Zentrum München, 81675 Munich, Germany.
authors.forename: Julie
authors.initials: J
authors.lastname: Lucifora
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Xia
authors.forename: Florian
authors.initials: F
authors.lastname: Reisinger
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.forename: Daniela
authors.initials: D
authors.lastname: Stadler
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Cheng
authors.forename: Martin F
authors.initials: MF
authors.lastname: Sprinzl
authors.forename: Herwig
authors.initials: H
authors.lastname: Koppensteiner
authors.forename: Zuzanna
authors.initials: Z
authors.lastname: Makowska
authors.forename: Tassilo
authors.initials: T
authors.lastname: Volz
authors.forename: Caroline
authors.initials: C
authors.lastname: Remouchamps
authors.forename: Wen-Min
authors.initials: WM
authors.lastname: Chou
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Thasler
authors.forename: Norbert
authors.initials: N
authors.lastname: Hüser
authors.forename: David
authors.initials: D
authors.lastname: Durantel
authors.forename: T Jake
authors.initials: TJ
authors.lastname: Liang
authors.forename: Carsten
authors.initials: C
authors.lastname: Münk
authors.forename: Markus H
authors.initials: MH
authors.lastname: Heim
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Browning
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Dejardin
authors.forename: Maura
authors.initials: M
authors.lastname: Dandri
authors.forename: Michael
authors.initials: M
authors.lastname: Schindler
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.forename: Ulrike
authors.initials: U
authors.lastname: Protzer
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D002467:Cell Nucleus / Q000821:virology; D003562:Cytidine / Q000378:metabolism; D003564:Cytidine Deaminase / Q000096:biosynthesis; D004270:DNA, Circular / Q000378:metabolism*; D004279:DNA, Viral / Q000378:metabolism*; D006509:Hepatitis B / Q000188:drug therapy*; D006515:Hepatitis B virus / Q000187:drug effects* / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology* / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D053259:Lymphotoxin beta Receptor / Q000819:agonists* / Q000037:antagonists & inhibitors; D016513:Mice, SCID; D015778:Minor Histocompatibility Antigens; D011506:Proteins; D015854:Up-Regulation
chemical_list: D000911:Antibodies, Monoclonal; D000998:Antiviral Agents; D004270:DNA, Circular; D004279:DNA, Viral; D016898:Interferon-alpha; D053259:Lymphotoxin beta Receptor; D015778:Minor Histocompatibility Antigens; D011506:Proteins; D003562:Cytidine; C121399:APOBEC3A protein, human; C495794:APOBEC3B protein, human; D003564:Cytidine Deaminase