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.
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)
A. 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.
B. 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.
C. 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.
D. 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.
E. 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.
F. 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.
G. 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.
H. 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.
I. 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.
J. 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.