Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA.

Lucifora, Julie, J; Xia, Yuchen, Y; Reisinger, Florian, F; Zhang, Ke, K; Stadler, Daniela, D; Cheng, Xiaoming, X; Sprinzl, Martin F, MF; Koppensteiner, Herwig, H; Makowska, Zuzanna, Z; Volz, Tassilo, T; Remouchamps, Caroline, C; Chou, Wen-Min, WM; Thasler, Wolfgang E, WE; Hüser, Norbert, N; Durantel, David, D; Liang, T Jake, TJ; Münk, Carsten, C; Heim, Markus H, MH; Browning, Jeffrey L, JL; Dejardin, Emmanuel, E; Dandri, Maura, M; Schindler, Michael, M; Heikenwalder, Mathias, M; Protzer, Ulrike, U     «

Lucifora, Julie, J; Xia, Yuchen, Y; Reisinger, Florian, F; Zhang, Ke, K; Stadler, Daniela, D; Cheng, Xiaoming, X; Sprinzl, Martin F, MF; Koppensteiner, Herwig, H; Makowska, Zuzanna, Z; Volz, Tassilo, T; Remouchamps, Caroline, C; Chou, Wen-Min, WM; Thasler, Wolfgang E, WE; Hüser, Norbert, N; Durantel, David, D; Liang, T Jake, TJ; Münk, Carsten, C; Heim, Markus H, MH; Browning, Jeffrey L, JL; Dejardin, Emmanuel, E; Dandri, Maura, M; Schindler, Michael, M; Heikenwalder, Mathias, M; Protzer, Ulrike,...     »

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

Current antiviral agents can control but not eliminate hepatitis B virus (HBV), because HBV establishes a stable nuclear covalently closed circular DNA (cccDNA). Interferon-? treatment can clear HBV but is limited by systemic side effects. We describe how interferon-? can induce specific degradation of the nuclear viral DNA without hepatotoxicity and propose lymphotoxin-? receptor activation as a therapeutic alternative. Interferon-? and lymphotoxin-? receptor activation up-regulated APOBEC3A an...     »