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. ; Peer reviewed