Project Description

TP15: Viral determinants and innate immunity in persistent hepatitis B virus and hepatitis D virus infections

Human hepatitis B (HBV) and hepatitis D viruses (HDV) cause persistent infections in more than 240 million people worldwide. Maintenance of persistence requires viral strategies to counteract intrinsic host immune responses. In this project, we aim to understand such responses on the molecular level in order to develop novel strategies to improve therapeutic outcomes of infection (functional cure). Specifically we will (i) investigate the impact of HBV integration on preservation of HBV and HDV templates (cccDNA and HDV RNA); (ii) elucidate the mechanism of innate immune sensing of replicating HDV RNA; (iii) uncover how IFNs suppress HDV spread during cell division.
Allweiss L, Testoni B, Yu M, Lucifora J, Ko C, Qu B, Lütgehetmann M, Guo H, Urban S, Fletcher SP, Protzer U, Levrero M, Zoulim F, Dandri M. (2023) Quantification of the hepatitis B virus cccDNA: evidence-based guidelines for monitoring the key obstacle of HBV cure. Gut. 72(5):972-983. doi: 10.1136/gutjnl-2022-328380.
Wedemeyer H, Schöneweis K,Bogomolov P, Blank A, Voronkova N, Stepanova T, Sagalova O, Chulanov V, Osipenko M, Morozov V, Geyvandova N, Sleptsova S, Bakulin IG, Khaertynova I, Rusanova M, Pathil A, Merle U, Bremer B, Allweiss L, Lempp FA, Urban S. (2023) Safety and efficacy of bulevirtide in combination with tenofovir disoproxil fumarate in patients with hepatitis B virus and hepatitis D virus coinfection (MYR202): a multicentre, randomised, parallel-group, open-label, phase 2 trial. Lancet Infect Dis. 23(1):117-129. doi: 10.1016/S1473-3099(22)00318-8.
Gillich N, Zhang Z, Binder M, Urban S, Bartenschlager R. (2022) Effect of variants in LGP2 on MDA5-mediated activation of interferon response and suppression of hepatitis D virus replication. J Hepatol. 21:S0168-8278(22)03113-0. doi: 10.1016/j.jhep.2022.08.041.
Zhang Z, Ni Y, Lempp FA, Walter L, Mutz P, Bartenschlager R, Urban S. (2022) Hepatitis D virus-induced interferon response and administered interferons control cell division-mediated virus spread. J Hepatol. 77(4):957-966. doi: 10.1016/j.jhep.2022.05.023.
Qu B, Nebioglu F, Leuthold MM, Ni Y, Mutz P, Beneke J, Erfle H, Vondran FWR, Bartenschlager R, Urban S. (2022) Dual role of neddylation in transcription of hepatitis B virus RNAs from cccDNA and production of viral surface antigen. JHEP Rep. 100551, ISSN 2589-5559,
Tu T, Zehnder B, Wettengel JM, Zhang H, Coulter S, Ho V, Douglas MW, Protzer U, George J, Urban S. (2022) Mitosis of hepatitis B virus-infected cells in vitro results in uninfected daughter cells. JHEP Rep. 15;4(9):100514. doi: 10.1016/j.jhepr.2022.100514.
Lempp FA, Roggenbach I, Nkongolo S, Sakin V, Schlund F, Schnitzler P, Wedemeyer H, Le Gal F, Gordien E, Yurdaydin C, Urban S. (2021) A rapid point-of-care test for the serodiagnosis of Hepatitis Delta virus infection viruses. 13(12): 2371. doi: 10.3390/v13122371.
Roggenbach I, Chi X, Lempp FA, Qu B, Walter L, Wu R, Gao X, Schnitzler P, Ding Y, Urban S, Niu J. (2021) HDV seroprevalence in HBsAg-positive patients in China occurs in hotspots and is not associated with HCV mono-infection. Viruses. 13(9):1799. doi: 10.3390/v13091799.
Oswald A, Chakraborty A, Ni Y, Wettengel JM, Urban S, Protzer U. (2021) Concentration of Na+-taurocholate-cotransporting polypeptide expressed after in vitro-transcribed mRNA transfection determines susceptibility of hepatoma cells for hepatitis B virus. Sci Rep. 5;11(1):19799. doi: 10.1038/s41598-021-99263-3.
Urban S, Neumann-Haefelin C, Lampertico P. (2021) Hepatitis D virus in 2021: virology, immunology and new treatment approaches for a difficult-to-treat disease. Gut. 70(9):1782-1794. doi: 10.1136/gutjnl-2020-323888.
Tu T, Zhang H, Urban S. (2021) Hepatitis B virus DNA integration: in vitro models for investigating viral pathogenesis and persistence. Viruses. 26;13(2):180. doi: 10.3390/v13020180.
Zhang Z, Urban S. (2021) New insights into HDV persistence: The role of interferon response and implications for upcoming novel therapies. J Hepatol. 74(3):686-699. doi: 10.1016/j.jhep.2020.11.032.
Tu T, Zehnder B, Qu B, Urban S. (2020) De novo synthesis of hepatitis B virus nucleocapsids is dispensable for the maintenance and transcriptional regulation of cccDNA. JHEP Rep. 14;3(1):100195.
Tu T, Zehnder B, Qu B, Ni Y, Main N, Allweiss L, Dandri M, Shackel N, George J, Urban S. A novel method to precisely quantify hepatitis B virus covalently closed circular (ccc)DNA formation and maintenance. Antiviral Res. 2020 Sep;181:104865. doi: 10.1016/j.antiviral.2020.104865. (TP15)

Dao Thi VL, Wu X, Belote RL, Andreo U, Takacs CN, Fernandez JP, Vale-Silva LA, Prallet S, Decker CC, Fu RM, Qu B, Uryu K, Molina H, Saeed M, Steinmann E, Urban S, Singaraja RR, Schneider WM, Simon SM, Rice CM. Stem cell-derived polarized hepatocytes. Nat Commun. 2020 Apr 3;11(1):1677. doi: 10.1038/s41467-020-15337-2. (TP22, TP15)

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(2):2265.
Giersch K, Bhadra OD, Volz T, Allweiss L, Riecken K, Fehse B, Lohse AW, Petersen J, Sureau C, Urban S, Dandri M, Lutgehetmann M. 2019. Hepatitis delta virus persists during liver regeneration and is ampli-fied through cell division both in vitro and in vivo. Gut. 68(1):150-157.
Ni Y, Zhang Z, Engelskircher L, Verch G, Tu T, Lempp FA, Urban S. 2019. Generation and characteriza-tion of a stable cell line persistently replicating and secreting the human hepatitis delta virus. Sci Rep. 9(1):10021.
Nkongolo S, Nußbaum L, Lempp FA, Wodrich H, Urban S, Ni Y. 2019. The retinoic acid receptor (RAR) α-specific agonist Am80 (tamibarotene) and other RAR agonists potently inhibit hepatitis B virus tran-scription from cccDNA. Antiviral Res. 168:146-155.
Zhang Z, Filzmayer C, Ni Y, Sultmann 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. 69(1):25-35.
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. 92(23): pii: e01117-18.
Mutz P, Metz P, Lempp FA, Bender S, Qu B, Schoneweis K, Seitz S, Tu T, Restuccia A, Frankish J, Dachert 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. 154(6):1791-1804.
Allweiss L, Volz T, Giersch K, Kah J, Raffa G, Petersen J, Lohse AW, Beninati C, Pollicino T, Urban S, Lutgehetmann M, Dandri M. 2018. Proliferation of primary human hepatocytes and prevention of hepati-tis B virus reinfection efficiently deplete nuclear cccDNA in vivo. Gut. 67(3):542-552.
Tu T, Budzinska MA, Vondran FWR, Shackel NA, Urban S. 2018. Hepatitis B virus DNA integration oc-curs early in the viral life cycle in an in vitro infection model via NTCP-dependent uptake of enveloped vi-rus particles. J Virol. 14;92(11). pii: e02007-17.
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. 66(3): 703-716.