Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA

J Lucifora, Y Xia, F Reisinger, K Zhang, D Stadler… - Science, 2014 - science.org
J Lucifora, Y Xia, F Reisinger, K Zhang, D Stadler, X Cheng, MF Sprinzl, H Koppensteiner…
Science, 2014science.org
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 …
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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