Specific and Nonhepatotoxic Degradation of Nuclear Hepatitis B Virus cccDNA

TLDR

Current antiviral agents control but do not eliminate HBV because the virus maintains stable nuclear cccDNA, and although interferon‑α can clear HBV, its systemic side effects limit use. The study aims to demonstrate that interferon‑α can specifically degrade nuclear HBV DNA without hepatotoxicity and to propose lymphotoxin‑β receptor activation as a therapeutic alternative. Interferon‑α and lymphotoxin‑β receptor activation induce APOBEC3A and APOBEC3B cytidine deaminases, which, via HBV core protein interaction with cccDNA, cause cytidine deamination, AP‑site formation, and subsequent degradation of cccDNA, preventing reactivation. The approach selectively degrades cccDNA without affecting genomic DNA, and inducing nuclear deaminases—e.g., through lymphotoxin‑β receptor activation—offers a new therapeutic strategy that could cure HBV when combined with existing antivirals.

Abstract

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.