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. Current antiviral treatment does not target established HBV cccDNA. Cytokines induce modification and degradation of HBV cccDNA and influence its activity. This may then finally allow curing hepatitis B. The overarching goal of this project is to understand cccDNA establishment, integrity and control in molecular detail to allow therapeutic targeting of cccDNA, which is the Holy Grail in “HBV Cure” research.
Namineni S, O'Connor T, Faure-Dupuy S, Johansen P, Riedl T, Liu K, Xu H, Singh I, Shinde P, Li F, Pandyra A, Sharma P, Ringelhan M, Muschaweckh A, Borst K, Blank P, Lampl S, Durantel D, Farhat R, Weber A, Lenggenhager D, Kündig TM, Staeheli P, Protzer U, Wohlleber D, Holzmann B, Binder M, Breuhahn K, Assmus LM, Nattermann J, Abdullah Z, Rolland M, Dejardin E, Lang PA, Lang KS, Karin M, Lucifora J, Kalinke U, Knolle PA, Heikenwalder M. 2020. A dual role for hepatocyte-intrinsic canonical NF-κB signaling in virus control. J Hepatol. 72(5):960-975. (TP05, TP06, TP11, TP13, TP14)

A. 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. * equal contribution.
B. 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 Research. 161:134-143
C. Bockmann JH, Stadler D, Xia Y, Ko C, Wettengel JM, Schulze zur Wiesch J, Dandri M, Protzer U. 2019. Compar-ative analysis of the antiviral effects mediated by type I and III interferons in hepatitis B virus infected hepato-cytes. J Inf Dis 220(4):567-577
D. Wing P, Davenne T, Wettengel J, Lai AG, Zhuang X, Chakraborty A, D’Arienzo V, Kramer C, Ko C, Harris LM, Schreiner S, Higgs M, Roessler S, Parish JL, Protzer U, Balfe P, Rehwinkel J, McKeating J.2019. A dual role for SAMHD1 in regulating HBV cccDNA and RT-dependent particle genesis. Life Sci Alliance. 2(2).
E. 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 an-tigen expressed in infected hepatocytes. Hepatology. 8(6):2089-2105.
F. 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 genome recycling and de novo secondary infection events maintain stable cccDNA levels. J Hepatol. 69(6):1231-1241.
G. 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. Nat Commun. 8(1): 2146. * equal contribution.
H. 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 HBV Infection. Sci Rep. 7(1):12715. * equal contribu-tion.
I. 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, Heikenwalder M, Protzer U. 2016. Interferon-γ and Tumor Necrosis Factor-α Produced by T cells Reduce the HBV Persistence Form, cccDNA, Without Cytolysis. Gastroenterology. 150(1):194-202.
J. Lucifora J*, Xia Y*, Reisinger F, Zhang K, Stadler D, Cheng X, Sprinzl M, Koppensteiner H, Li Y, Makowska Z, Volz T, Remouchamps C, Chou W-M, Thasler W, Hüser N, Durantel D, Münk C, Heim MH, Browning 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(6176):1121-1128. * equal contribution.