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发帖数: 64 | 1 http://www.sciencemag.org/content/343/6176/1221.abstract
Research Article
Specific and Nonhepatotoxic Degradation of Nuclear Hepatitis B Virus cccDNA
Lucifora J1, Xia Y, Reisinger F, Zhang K, Stadler D, Cheng X, Sprinzl MF,
Koppensteiner H, Makowska Z, Volz T, Remouchamps C, Chou WM, Thasler WE, Hü
ser N, Durantel D, Liang TJ, Münk C, Heim MH, Browning JL, Dejardin E,
Dandri M, Schindler M, Heikenwalder M, Protzer U
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. |
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