Publication Date:
2014-02-22
Description:
Current antiviral agents can control but not eliminate hepatitis B virus (HBV), because HBV establishes a stable nuclear covalently closed circular DNA (cccDNA). Interferon-alpha treatment can clear HBV but is limited by systemic side effects. We describe how interferon-alpha can induce specific degradation of the nuclear viral DNA without hepatotoxicity and propose lymphotoxin-beta receptor activation as a therapeutic alternative. Interferon-alpha and lymphotoxin-beta 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-beta receptor activation-allows the development of new therapeutics that, in combination with existing antivirals, may cure hepatitis B.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- Huser, Norbert -- Durantel, David -- Liang, T Jake -- Munk, Carsten -- Heim, Markus H -- Browning, Jeffrey L -- Dejardin, Emmanuel -- Dandri, Maura -- Schindler, Michael -- Heikenwalder, Mathias -- Protzer, Ulrike -- New York, N.Y. -- Science. 2014 Mar 14;343(6176):1221-8. doi: 10.1126/science.1243462. Epub 2014 Feb 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Virology, Technische Universitat Munchen-Helmholtz Zentrum Munchen, 81675 Munich, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24557838" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antibodies, Monoclonal
;
Antiviral Agents/*pharmacology/therapeutic use
;
Cell Line
;
Cell Nucleus/virology
;
Cytidine/metabolism
;
Cytidine Deaminase/biosynthesis
;
DNA, Circular/*metabolism
;
DNA, Viral/*metabolism
;
Hepatitis B/*drug therapy
;
Hepatitis B virus/*drug effects/metabolism
;
Hepatocytes/*drug effects/metabolism/virology
;
Humans
;
Interferon-alpha/*pharmacology/therapeutic use
;
Liver/drug effects/metabolism/virology
;
Lymphotoxin beta Receptor/*agonists/antagonists & inhibitors
;
Mice, SCID
;
Proteins
;
Up-Regulation
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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