Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA
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Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. / Lucifora, Julie; Xia, Yuchen; Reisinger, Florian; Zhang, Ke; Stadler, Daniela; Cheng, Xiaoming; Sprinzl, Martin F; Koppensteiner, Herwig; Makowska, Zuzanna; Volz, Tassilo; Remouchamps, Caroline; Chou, Wen-Min; Thasler, Wolfgang E; Hüser, Norbert; Durantel, David; Liang, T Jake; Münk, Carsten; Heim, Markus H; Browning, Jeffrey L; Dejardin, Emmanuel; Dandri, Maura; Schindler, Michael; Heikenwalder, Mathias; Protzer, Ulrike.
in: SCIENCE, Jahrgang 343, Nr. 6176, 14.03.2014, S. 1221-1228.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA
AU - Lucifora, Julie
AU - Xia, Yuchen
AU - Reisinger, Florian
AU - Zhang, Ke
AU - Stadler, Daniela
AU - Cheng, Xiaoming
AU - Sprinzl, Martin F
AU - Koppensteiner, Herwig
AU - Makowska, Zuzanna
AU - Volz, Tassilo
AU - Remouchamps, Caroline
AU - Chou, Wen-Min
AU - Thasler, Wolfgang E
AU - Hüser, Norbert
AU - Durantel, David
AU - Liang, T Jake
AU - Münk, Carsten
AU - Heim, Markus H
AU - Browning, Jeffrey L
AU - Dejardin, Emmanuel
AU - Dandri, Maura
AU - Schindler, Michael
AU - Heikenwalder, Mathias
AU - Protzer, Ulrike
PY - 2014/3/14
Y1 - 2014/3/14
N2 - 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.
AB - 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.
KW - Animals
KW - Antibodies, Monoclonal
KW - Antiviral Agents
KW - Cell Line
KW - Cell Nucleus
KW - Cytidine
KW - Cytidine Deaminase
KW - DNA, Circular
KW - DNA, Viral
KW - Hepatitis B
KW - Hepatitis B virus
KW - Hepatocytes
KW - Humans
KW - Interferon-alpha
KW - Liver
KW - Lymphotoxin beta Receptor
KW - Mice, SCID
KW - Proteins
KW - Up-Regulation
U2 - 10.1126/science.1243462
DO - 10.1126/science.1243462
M3 - SCORING: Journal article
C2 - 24557838
VL - 343
SP - 1221
EP - 1228
JO - SCIENCE
JF - SCIENCE
SN - 0036-8075
IS - 6176
ER -