Specific and Nonhepatotoxic Degradation of Nuclear Hepatitis B Virus cccDNA.

[en] Current antivirals can control but not eliminate hepatitis-B-virus (HBV), because HBV establishes a stable nuclear cccDNA. Interferon-alpha treatment can clear HBV but is limited by systemic side effects. Here, 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 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-beta-receptor activation - allows development of new therapeutics that combined with existing antivirals may cure hepatitis B.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Lucifora, Julie

Xia, Yuchen

Reisinger, Florian

Zhang, Ke

Stadler, Daniela

Cheng, Xiaoming

Sprinzl, Martin F.

Koppensteiner, Herwig

Makowska, Zuzanna

Volz, Tassilo

More authors (14 more)

Language :

English

Title :

Specific and Nonhepatotoxic Degradation of Nuclear Hepatitis B Virus cccDNA.

Publication date :

14 March 2014

Journal title :

Science

ISSN :

0036-8075

eISSN :

1095-9203

Publisher :

American Association for the Advancement of Science, Washington, United States - District of Columbia

Volume :

343

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 05 March 2015

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