Project Description

TP14: Means of modification and degradation of hepatitis B virus cccDNA

HBV persists by establishing a covalently closed circular (ccc) DNA form in the nucleus of infected hepatocytes, which serves as transcription template for all viral RNAs. We recently demonstrated that nuclear HBV DNA is specifically degraded by cellular endonucleases after it has been modified by cytokine-induced, nuclear APOBEC3 (A3) family deaminases A3A and A3B (Lucifora, Xia et al. Science 2014; Xia, Stadler et al. Gastroenterology 2015). This project aims at understanding of why the nuclear HBV DNA is degraded and not repaired and how specificity of this process can be ensured, which seems a prerequisite for exploiting this cell-intrinsic defence for curative approaches.
Protzer U. 2017. Viral hepatitis: The bumpy road to animal models for HBV infection. Nat Rev Gastroenterol Hepatol. 14(6):327-328. Review
Ko C, Michler T, Protzer U. 2017. Novel viral and host targets to cure hepatitis B. Curr Opin Virol. 24:38-45. Review.
Xia Y, Protzer U. 2017. Control of Hepatitis B Virus by Cytokines. Viruses. 9(1). pii: E18. doi: 10.3390/v9010018. Review.
Protzer U, Knolle P. 2016. "To Be or Not to Be": Immune Tolerance in Chronic Hepatitis B. Gastroenterology. 151(5):805-806. doi: 10.1053/j.gastro.2016.09.038
Michler T, Große S, Mockenhaupt S, Röder N, Stückler F, Knapp B, Ko C, Heikenwalder M, Protzer U, Grimm D. 2016. Blocking sense-strand activity improves potency, safety and specificity of anti-hepatitis B virus short hairpin RNA. EMBO Mol Med. 8(9):1082-98. doi: 10.15252/emmm.201506172.
Xia Y*, Stadler D*, Lucifora J, Reisinger F, Webb D, Hösel M, Michler T, Wisskirchen K, Cheng X, Zhang K, Chao W-M, Wettengel J, Malo A, Bohne F, Hoffmann D, Eyer F, Thimme R, Thasler WE, Heikenwal- der M, Protzer U. Interferon-γ and Tumor Necrosis Factor-α Produced by T cells Reduce the HBV Persis- tence Form, cccDNA, Without Cytolysis. Gastroenterology, 2015 Sep 25. pii: S0016-5085(15)01382-7. Doi. *equal contribution
Lucifora J*, Xia Y*, Reisinger F, Zhang K, Stadler D, Cheng X, Sprinzl M, Koppensteiner H, Li Y, Makow- ska Z, Volz T, Remouchamps C, Chou W-M, Thasler W, Hüser N, Durantel D, Münk C, Heim MH, Brown- ing JL, Dejardin E, Dandri M, Schindler M, Heikenwalder M*, Protzer U*. 2014. Specific and non- hepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science 343:1121-1128.
Krebs K, Böttinger N, Huang LR, Chmielewski M, Arzberger S, Gasteiger G, Jäger C, Schmitt E, Bohne F, Aichler M, Uckert W, Abken H, Heikenwalder M, Knolle PA, Protzer U. 2013. T cells expressing a chimeric antigen receptor that binds hepatitis B virus envelope proteins control virus replication in mice. Gastroenterology 145:456-65.
Huang LR, Gäbel YA, Graf S, Arzberger S, Kurts C, Heikenwalder M, Knolle PA, Protzer U. 2012. Trans- fer of HBV genomes using low doses of adenovirus vectors leads to persistent infection in immune com- petent mice. Gastroenterology 142:1447-50.
Ebert G, Poek H, Lucifora J, Barschuk N, Esser K, Esposito I, Hartmann G, Protzer U. 2011. siRNAs designed to activate retinoic acid–inducible protein I control hepatitis B virus in primary human hepatocytes and in mice. Gastroenterology 141:696-706.
Lucifora J, Arzberger S, Durantel D, Belloni L, Strubin M, Levrero M, Zoulim F, Hantz O, Protzer U. 2011. Hepatitis B Virus X protein is essential to initiate and maintain virus replication after infection. J Hepatology 55: 996-1003.
Hösel M, Quasdorff M, Webb D, Zedler U, Broxtermann M, Tedjokusumo R, Esser K, Arzberger S, Wieg- mann K, Kirschning CJ, Langenkamp A, Rose-John S, Protzer U. 2009. Not interferon, but IL-6 controls early gene expression in Hepatitis B virus (HBV) infection. Hepatology 50:1773-1782.
Quasdorff M, Hösel M, Odenthal M, Zedler U, Bohne F, Gripon P, Dienes HP, Stippel D, Goeser T, Protzer U. 2008. A concerted action of HNF1 α and HNF4α links hepatitis B virus replication to hepatocyte differentiation. Cellular Micobiology 10:1478-1490.
Bohne F, Chmielewski M, Ebert G, Wiegmann K, Kürschner T, Schulze A, Urban S, Krönke M, Abken H, Protzer U. 2008. T cells redirected against hepatitis B virus surface proteins eliminate infected hepato- cytes. Gastroenterology 134: 239-47.
J.Protzer U, Nassal M, Chiang PW, Kirschfink M, Schaller H. 1999. Interferon gene transfer by a novel hepatitis B virus vector efficiently suppresses wildtype-virus infection. Proc Natl Acad Sci U S A., 96: 10818-10823.