Current antivirals can control but not eliminate hepatitis-B-virus (HBV), because HBV establishes a stable nuclear cccDNA. Interferon-αtreatment can clear HBV but is limited by systemic side effects. IFN-αis known to exert transcriptional, post-transcriptional and epigenetic antiviral effects on HBV. We study how interferon-αcan induce specific degradation of the nuclear viral DNA without hepatotoxicity and propose lymphotoxin-β-receptor activation as a therapeutic alternative. Interferon-αand 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. On the other hand, genomic DNA was not affected. Our data indicate that cccDNA degradation is possible and can be induced without side-effects on the infected host cell. An important task will be testing of combinations of nucleos(t)ide analogues with novel anti-viral strategies (e.g. LTβR agonists or adoptive T-cell therapy) to activate A3A or A3B to cure hepatitis B. 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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