128 Cure of HBV infection: can APOBEC3 deaminases mediate it?

Current antivirals cannot efficiently control but not eliminate hepatitis B virus (HBV) in the 300 million carriers at risk to develop liver diseases and cancer, because HBV establishes a stable nuclear cccDNA in infected hepatocytes. Interferon can clear HBV but therapeutic dosing is limited by side effects. We found a mechanism by which nuclear viral DNA can specifically be degraded. In HBV-infected cells and primary human hepatocytes, human liver-needle biopsies and in vivo mouse models, interferon and even at much lower doses lymphotoxin—receptor activation up-regulated nuclear APOBEC3 family deaminases. Cytidine-deamination resulted in apurinic/apyrimidinic site formation and finally cccDNA degradation. No deamination was detected in genomic DNA since HBV-core protein targeted the APOBEC3 protein to cccDNA. Inducing nuclear APOBEC3 deaminases eg, by triggering the lymphotoxin—receptor pathway will be of high interest for the development of new therapeutics. The combination with existing antivirals shows great promise to eliminate the virus in chronic hepatitis B.