Project Description

TP15: Hepatitis B virus X-protein-mediated transcriptional regulation and stability of cccDNA

Hepatitis B Virus (HBV) causes persistent infections of the liver. The template of HBV is a nuclear episome called cccDNA. Transcription of viral genes from cccDNA is regulated by the HBV X-protein through a mostly unknown mechanism probably counteracting epigenetic silencing processes. In addition to this process, cccDNA might vanish during cell division. Based on previous results showing that HBx-mediated activation of cccDNA-transcription requires DDB1 we aim at elucidating further details of this regulation. We will also apply NTCP-expressing cell lines to study cccDNA stability during cell division and determine the contribution of this process to its clearance.
Lempp FA, Schlund F, Rieble L, Nussbaum L, Link C, Zhang Z, Ni Y, Urban S. 2019. Recapitulation of HDV infection in a fully permissive hepatoma cell line allows efficient drug evaluation. Nat Commun. 10(1):2265. doi: 10.1038/s41467-019-10211-2.
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.
Schuch A, Salimi Alizei E, Heim K, Wieland D, Kiraithe MM, Kemming J, Llewellyn-Lacey S, Sogukpinar Ö, Ni Y, Urban S, Zimmermann P, Nassal M, Emmerich F, Price DA, Bengsch B, Luxenburger H, Neumann-Haefelin C, Hofmann M, Thimme R. 2019. Phenotypic and functional differences of HBV core-specific versus HBV polymerase-specific CD8+ T cells in chronically HBV-infected patients with low viral load. Gut. 2019 Jan 8. pii: gutjnl-2018-316641. doi: 10.1136/gutjnl-2018-316641. (Epub ahead of print)
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
Qu B, Ni Y, Lempp FA, Vondran FWR, Urban S. 2018. T5 exonuclease hydrolysis of Hepatitis B Virus replicative intermediates allows reliable quantification and fast drug efficacy testing of covalently closed circular DNA by PCR. J Virol. 2018 Sep 19. pii: JVI.01117-18. doi: 10.1128/JVI.01117-18. (Epub ahead of print)
Tu T, Budzinska MA, Vondran FWR, Shackel NA, Urban S. 2018. Hepatitis B virus DNA integration occurs early in the viral life cycle in an in vitro infection model via NTCP-dependent uptake of enveloped virus particles. J Virol. 2018 Feb 7. pii: JVI.02007-17. doi: 10.1128/JVI.02007-17. [Epub ahead of print] PMID: 29437961
Tu T, Urban S. 2018. Virus entry and its inhibition to prevent and treat hepatitis B and hepatitis D virus infections. Curr Opin Virol. 30:68-79. doi: 10.1016/j.coviro.2018.04.004.Review.
Budzinska MA, Shackel NA, Urban S, Tu T. 2018. Sequence analysis of integrated hepatitis B virus DNA during HBeAg-seroconversion. Emerg Microbes Infect. 7(1):142. doi: 10.1038/s41426-018-0145-7.
Budzinska MA, Shackel NA, Urban S, Tu T. 2018. Cellular Genomic Sites of Hepatitis B Virus DNA Integration. Genes (Basel). 9(7). pii: E365. doi: 10.3390/genes9070365. Review.
Zhang Z, Filzmayer C, Ni Y, Sültmann H, Mutz P, Hiet MS, Vondran FWR, Bartenschlager R, Urban S. 2018. Hepatitis D virus replication is sensed by MDA5 and induces IFN-β/λ responses in hepatocytes. J Hepatol. 2018 Mar 8. pii: S0168-8278(18)30143-0. doi: 10.1016/j.jhep.2018.02.021. (Epub ahead of print)
Mutz P, Metz P, Lempp FA, Bender S, Qu B, Schöneweis K, Seitz S, Tu T, Restuccia A, Frankish J, Dächert C, Schusser B, Koschny R, Polychronidis G, Schemmer P, Hoffmann K, Baumert TF, Binder M, Urban S, Bartenschlager R. 2018. HBV Bypasses the Innate Immune Response and Does not Protect HCV From Antiviral Activity of Interferon. Gastroenterology. 2018 Jan 31. pii: S0016-5085(18)30112-4. doi: 10.1053/j.gastro.2018.01.044. (Epub ahead of print).
Lempp FA, Urban S. 2017. Hepatitis Delta Virus: Replication Strategy and Upcoming Therapeutic Options for a Neglected Human Pathogen. Viruses. 9(7). pii: E172. doi: 10.3390/v9070172. Review.
Tu T, Budzinska MA, Shackel NA, Urban S. H. 2017. BV DNA Integration: Molecular Mechanisms and Clinical Implications. Viruses. 9(4). pii: E75. doi: 10.3390/v9040075. Review.
Lempp FA, Wiedtke E, Qu B, Roques P, Chemin I, Vondran FW, Le Grand R, Grimm D, Urban S. 2017. Sodium taurocholate cotransporting polypeptide is the limiting host factor of Hepatitis B Virus infection in macaque and pig hepatocytes. Hepatology. 2017 Feb 13. doi: 10.1002/hep.29112.
Hoh A, Heeg M, Ni Y, Schuch A, Binder B, Hennecke N, Blum HE, Nassal M, Protzer U, Hofmann M, Urban S, Thimme R. 2015. HBV-infected HepG2hNTCP cells serve as a novel immunological tool to analyse the antiviral efficacy of CD8+ T cells in vitro. J Virol 89:7433-8
Slijepcevic D, Kaufman C, Wichers CG, Giglioni EH, Lempp F, Duijst S, de Waart DR, Oude Elferink RP, Mier W, Stieger B, Beuers U, Urban S, van de Graaf SF. 2015. Impaired uptake of conjugated bile acids and Hepatitis B Virus pres1-binding in Na+-taurocholate cotransporting polypeptide knockout mice. Hepatology. 62(1):207-19. doi: 10.1002/hep.27694.
Urban S, Bartenschlager R, Kubitz R, Zoulim F. 2014. Strategies to Inhibit Entry of HBV and HDV into Hepatocytes. Gastroenterology 147:48-64.
Ni Y, Lempp FA, Mehrle S, Nkongolo S, Kaufman C, Fälth M, Nassal M, Kubitz, R, Sültmann H, Urban S. 2014. Hepatitis B and D virus exploits sodium taurocholate co-transporting polypeptide (NTCP) for entering hepatocytes in a species-specific manner. Gastroenterology 146:1070-83.
Nkongolo S, Ni Y, Lempp FA, Kaufman C, Lindner T, Esser-Nobis K, Lohmann V, Mier W, Mehrle S, Urban S. 2014. Cyclosporin A inhibits Hepatitis B and Hepatitis D Virus entry by Cyclophilin-independent interference with sodium taurocholate co-transporting polypeptide (NTCP) receptor. J Hepatol 60:723-31.
Urban S, Bogomolov P, Voronkova N, Allweis L, Dandri M, Schwab M, Lempp FA, Haag M, Wedemeyer H, Alexandrov A. 2014. A proof-of-concept Phase IIa clinical trial with the HBV/HDV entry inhibitor Myrcludex B. Hepatology 60 (Suppl): LB20.
Schulze A, Mills, K, Weiss TS, Urban S. 2012. Hepatocyte polarization is essential for the productive entry of the hepatitis B virus. Hepatology 55:373-383.
Petersen J, Dandri M, Mier W, Lütgehetman M, Volz T, von Weizsäcker F, Haberkorn U, Fischer L, Pollock JM, Erbes B, Seitz S, Urban S. 2008. Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein. Nature Biotechnology 26:335-341.
Gripon P, Rumin S, Urban S, Le Seyec J, Glaise D, Cannie I, Guyomard C, Lucas J, Trepo C, Guguen- Guillouzo C. 2002. Infection of a human hepatoma cell line by hepatitis B virus. PNAS, USA 99:15655-60.
Urban S, Hildt E, Eckerskorn C, Sirma H, Kekule A, Hofschneider PH. 1997. Isolation and characterization of hepatitis B virus X-protein from a baculovirus expression system. Hepatology 26:1045-53.