Cytidine Deamination and cccDNA Degradation: A New Approach for Curing HBV?

Current antiviral agents can control but not eliminate hepatitis B virus (HBV), because HBV establishes a stable nuclear covalently closed circular DNA (cccDNA). Interferon-a treatment can clear HBV but is limited by systemic side effects. We describe how interferon-a can induce specific degradation of the nuclear viral DNA without hepatotoxicity and propose lymphotoxin-b receptor activation as a therapeutic alternative. Interferon-a and lymphotoxin-beta receptor activation upregulated 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-b receptor activationallows the development of new therapeutics that, in combination with existing antivirals, may cure hepatitis B.