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Lucifora, J. ; Xia, Y. ; Reisinger, F. ; Zhang, K. ; Stadler, D. ; Cheng, X. ; Sprinzl, M.F. ; Koppensteiner, H. ; Makowska, Z.* ; Volz, T.* ; Remouchamps, C.* ; Chou, W.-M. ; Thasler, W.E.* ; Hüser, N.* ; Durantel, D.* ; Liang, T.J.* ; Münk, C.* ; Heim, M.H.* ; Browning, J.L.* ; Dejardin, E.* ; Dandri, M.* ; Schindler, M. ; Heikenwälder, M. ; Protzer, U.

Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA.

Science 343, 1221-1228 (2014)
Postprint DOI PMC
Open Access Green
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Lymphotoxin-beta-receptor; Gene-expression; Hepatocellular-carcinoma; Cytidine Deaminases; Human Hepatocytes; Transgenic Mice; Hbv Infection; Foreign Dna; In-vitro; Replication
Language english
Publication Year 2014
HGF-reported in Year 2014
ISSN (print) / ISBN 0036-8075
e-ISSN 1095-9203
Journal Science
Quellenangaben Volume: 343, Issue: 6176, Pages: 1221-1228 Article Number: , Supplement: ,
Publisher American Association for the Advancement of Science (AAAS)
Publishing Place Washington
Reviewing status Peer reviewed
Institute(s) Institute of Virology (VIRO)
POF-Topic(s) 30203 - Molecular Targets and Therapies
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s) Immune Response and Infection
PSP Element(s) G-502700-003
G-502700-006
G-551600-001
DOI 10.1126/science.1243462
WOS ID WOS:000332728500030
PubMed ID 24557838
Erfassungsdatum 2014-02-21
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