Project Description
Public­ations

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.
Hu J, Protzer U, Siddiqui A. 2019. Revisiting Hepatitis B virus: Challenges of Curative Therapies. J Virol. 2019 Aug 2. pii: JVI.01032-19. doi: 10.1128/JVI.01032-19. [Epub ahead of print] Review.
Kosinska AD, Moeed A, Kallin N, Festag J, Su J, Steiger K, Michel ML, Protzer U, Knolle PA. 2019. Synergy of therapeutic heterologous prime-boost hepatitis B vaccination with CpG-application to improve immune control of persistent HBV infection. Sci Rep.9(1):10808. doi: 10.1038/s41598-019-47149-w.
Wing PA, Davenne T, Wettengel J, Lai AG, Zhuang X, Chakraborty A, D'Arienzo V, Kramer C, Ko C, Harris JM, Schreiner S, Higgs M, Roessler S, Parish JL, Protzer U, Balfe P, Rehwinkel J, McKeating JA. 2019. A dual role for SAMHD1 in regulating HBV cccDNA and RT-dependent particle genesis. Life Sci Alliance. 2(2). pii: e201900355. doi: 10.26508/lsa.201900355.
Bockmann JH, Stadler D, Xia Y, Ko C, Wettengel JM, Zur Wiesch JS, Dandri M, Protzer U. 2019. Comparative analysis of the antiviral effects mediated by type I and III interferons in hepatitis B virus infected hepatocytes. J Infect Dis. 2019 Mar 29. pii: jiz143. doi: 10.1093/infdis/jiz143. (Epub ahead of print)
Wisskirchen K, Kah J, Malo A, Asen T, Volz T, Allweiss L, Wettengel JM, Lütgehetmann M, Urban S, Bauer T, Dandri M, Protzer U. 2019. T cell receptor grafting allows virological control of Hepatitis B virus infection. J Clin Invest. 129(7):2932-2945. doi: 10.1172/JCI120228.
Karimzadeh H, Kiraithe MM, Oberhardt V, Alizei ES, Bockmann J, Zur Wiesch JS, Budeus B, Hoffmann D, Wedemeyer H, Cornberg M, Krawczyk A, Rashidi-Alavijeh J, Rodríguez-Frías F, Casillas R, Buti M, Smedile A, Alavian SM, Heinold A, Emmerich F, Panning M, Gostick E, Price DA, Timm J, Hofmann M, Raziorrouh B, Thimme R, Protzer U, Roggendorf M, Neumann-Haefelin C. 2019. Mutations in Hepatitis D Virus Allow it to Escape Detection by CD8+ T Cells and Evolve at the Population Level. Gastroenterology. 2019 Feb 12. pii: S0016-5085(19)30366-X. doi: 10.1053/j.gastro.2019.02.003. (Epub ahead of print)
Xia Y, Schlapschy M, Morath V, Roeder N, Vogt EI, Stadler D, Cheng X, Dittmer U, Sutter K, Heikenwalder M, Skerra A, Protzer U. 2019. PASylated interferon α efficiently suppresses hepatitis B virus and induces anti-HBs seroconversion in HBV-transgenic mice. Antiviral Res. 161:134-143. doi: 10.1016/j.antiviral.2018.11.003
Bartenschlager R, Urban S, Protzer U. 2019. Towards curative therapy of chronic viral hepatitis. Z Gastroenterol. 57(1):61-73. doi: 10.1055/a-0824-1576
Gehring AJ, Protzer U. 2019. Targeting Innate and Adaptive Immune Responses to Cure Chronic HBV Infection. Gastroenterology. 2019 156(2):325-337. doi: 01.1053/j.gastro.2018.10.032.
Velkov S, Ott JJ, Protzer U, Michler T. 2018. The Global Hepatitis B Virus Genotype Distribution Approximated from Available Genotyping Data. Genes (Basel). 9(10). pii: E495. doi: 10.3390/genes9100495.
Lazarus J, Block T, Bréchot C, Kramvis A, Miller V, Ninburg M, Penicaud MC, Protzer U, Razavi H, Thomas L, Wallace J, Cowie B. 2018. The hepatitis B epidemic and the urgent need for cure preparedness. Nature Reviews Gastroenterology and Hepatology. 15(9): 517-518.
Ko C, Chakraborty A, Chou WM, Hasreiter J, Wettengel JM, Stadler D, Bester R, Asen T, Zhang K, Wisskirchen K, McKeating JA, Ryu WS, Protzer U. 2018. Hepatitis B virus (HBV) genome recycling and de novo secondary infection events maintain stable cccDNA levels. J Hepatol. 2018 Aug 21. pii: S0168-8278(18)32294-3. doi: 10.1016/j.jhep.2018.08.012. (Epub ahead of print)
Manske K, Kallin N, König V, Schneider A, Kurz S, Bosch M, Welz M, Cheng RL, Bengsch B, Steiger K, Protzer U, Thimme R, Knolle PA, Wohlleber D. 2018. Outcome of anti-viral immunity in the liver is shaped by the level of antigen expressed in infected hepatocytes. Hepatology. 2018 May 5. doi: 10.1002/hep.30080. (Epub ahead of print)
Dembek C, Protzer U, Roggendorf M. 2018. Overcoming immune tolerance in chronic hepatitis B by therapeutic vaccination. Curr Opin Virol. 2018 May 8;30:58-67. doi: 10.1016/j.coviro.2018.04.003. (Epub ahead of print) Review.
Esser K, Lucifora J, Wettengel J, Singethan K, Glinzer A, Zerneke A, Protzer U. 2018. Lipase inhibitor orlistat prevents hepatitis B virus infection by targeting an early step in the virus life cycle. Antiviral Research 151: 4-7.
Karimzadeh H, Kiraithe MM, Kosinska AD, Glaser M, Fiedler M, Oberhardt V, Salimi Alizei E, Hofmann M, Mok JY, Nguyen M, van Esch WJE, Budeus B, Grabowski J, Homs M, Olivero A, Keyvani H, Rodríguez-Frías F, Tabernero D, Buti M, Heinold A, Alavian SM, Bauer T, Schulze Zur Wiesch J, Raziorrouh B, Hoffmann D, Smedile A, Rizzetto M, Wedemeyer H, Timm J, Antes I, Neumann-Haefelin C, Protzer U, Roggendorf M. 2018. Amino acid substitutions within HLA-B*27-restricted T cell epitopes prevent recognition by hepatitis delta virus-specific CD8+ T cells. J Virol. 2018 Apr 18. pii: JVI.01891-17. doi: 10.1128/JVI.01891-17. (Epub ahead of print)
Lorentzen A, Becker PF, Kosla J, Saini M, Weidele K, Ronchi P, Klein C, Wolf MJ, Geist F, Seubert B, Ringelhan M, Mihic-Probst D, Esser K, Roblek M, Kuehne F, Bianco G, O'Connor T, Müller Q, Schuck K, Lange S, Hartmann D, Spaich S, Groß O, Utikal J, Haferkamp S, Sprick MR, Damle-Vartak A, Hapfelmeier A, Hüser N, Protzer U, Trumpp A, Saur D, Vartak N, Klein CA, Polzer B, Borsig L, Heikenwalder M. 2018. Single cell polarity in liquid phase facilitates tumour metastasis. Nat Commun. 2018 Feb 28;9(1):887. doi: 10.1038/s41467-018-03139-6.
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.
Golsaz-Shirazi F, Amiri MM, Farid S, Bahadori M, Bohne F, Altstetter S, Wolff L, Kazemi T, Khoshnoodi J, Hojjat-Farsangi M, Chudy M, Jeddi-Tehrani M, Protzer U, Shokri F. 2017. Construction of a hepatitis B virus neutralizing chimeric monoclonal antibody recognizing escape mutants of the viral surface antigen (HBsAg). Antiviral Res. 144:153-163.
Xia Y, Protzer U. 2017. Control of Hepatitis B Virus by Cytokines. Viruses. 9(1). pii: E18. doi: 10.3390/v9010018. Review.
Burwitz B**, Wettengel J**, Mück-Häusl M, Ringelhan M, Ko C, Festag MM, Hammond KB, Northrup M, Bimber BN, Jacob T, Reed JS, Reed N, Park B, Moller-Tank S, Esser K, Greene JM, Wu HL, Abdulhaqq S, Webb G, Sutton WF, Klug A, Swanson T, Legasse AW, Vu TQ, Asokan A, Haigwood NL, Protzer U**, Sacha J**. 2017. Hepatocytic Expression of Human Sodium-Taurocholate Cotransporting Polypeptide Enables Hepatitis B Virus Infection of Macaques. Nature Communications 8 (1): 2146.** equal contribution
Li Y, Xia Y, Han M, Chen G, Zhang D, Thasler W, Protzer U**, Ning Q**. 2017. IFN-α-mediated Base Excision Repair Pathway Correlates with Antiviral Response Against Hepatitis B Virus Infection. Scientific Reports 7(1):12715. doi: 10.1038/s41598-017-13082-z.**co-corresponding authors.
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.