Virological and immunological mechanisms of hepatitis C virus persistence
Zusammenfassung der Projektergebnisse
Persistent infections with hepatotropic viruses are still major risk factors for chronic liver diseases. Worldwide, ~58 million are persistently infected with HCV. Although acute infections with this virus are asymptomatic in the majority of cases or associated with rather mild symptoms, the clinical challenge of infections especially with HCV is the high rate of persistence, which is a major predisposing factor for serious liver damage including hepato-steatosis, liver cirrhosis and hepatocellular carcinoma. Although this phenomenon argues for viral strategies of immune evasion, the molecular mechanisms underlying inefficient virus control were poorly defined at the time of application and no direct antiviral therapy was available. Within the frame of the two funding periods of this project, we gained important insights into the process how persistence by HCV is established and maintained. We established a cell culture system mimicking viral persistence and obtained evidence that HCV might exploit the stochastic nature of the interferon (IFN) response. We could demonstrate persistent HCV replication and viremia in this cell culture model for up to 3 months. Importantly, long-term IFN alpha treatment reduced HCV replication up to 1,000-fold, but did not eliminate the virus that rebounded after IFN withdrawal, reminiscent to what is found in chronic hepatitis C patients. Concerning the induction of the IFN response, we have found that HCV activates RIG-I and Mda5 in a consecutive manner. Interestingly the viral protein NS5A, with domain 2 playing a yet undescribed key role in this process, efficiently suppresses RIG-I and especially Mda5 activation. By using live cell imaging, we found that HCV triggers induction of stress granules in an IFNα-dependent manner. Their assembly and disassembly is highly dynamic which is important for cell survival and thus, persistence. We also observed that HCV replication is sensitive both to type I IFN and to IFN-lambda with the latter having a stronger antiviral effect in long-term differentiated human hepatocytic cells. By using a siRNA-based screen, we have reported that HCV replication is suppressed by a concerted action of several IFN-stimulated genes (ISGs) including nitric oxide synthase 2 (NOS2). The results of these studies contributed to a better understanding of the strategies used by HCV to overcome innate immune responses.
Projektbezogene Publikationen (Auswahl)
- 2011. Experimental models to study the immunobiolodoi: J Gen Virol. 92(Pt 3):477-93
Jo J, Lohmann V, Bartenschlager R, Thimme R
(Siehe online unter https://doi.org/10.1099/vir.0.027987-0) - 2011. Molecular mechanism of signal perception and integration by the innate immune sensor retinoic acid-inducible gene-I (RIG-I). J Biol Chem 286(31):27278-87
Binder M, Eberle F, Seitz S, Mücke N, Hüber CM, Kiani N, Kaderali L, Lohmann V, Dalpke A, Bartenschlager R
(Siehe online unter https://doi.org/10.1074/jbc.M111.256974) - 2012. Dynamic oscillation of translation and stress granule formation mark the cellular response to virus infection. Cell Host Microbe. 12(1):71-85
Ruggieri A, Dazert E, Metz P, Hofmann S, Bergeest JP, Mazur J, Bankhead P, Hiet MS, Kallis S, Alvisi G, Samuel CE, Lohmann V, Kaderali L, Rohr K, Frese M, Stoecklin G, Bartenschlager R
(Siehe online unter https://doi.org/10.1016/j.chom.2012.05.013) - 2012. Identification of type I and type II interferon-induced effectors controlling hepatitis C virus replication. Hepatology 56(6):2082-93
Metz P, Dazert E, Ruggieri A, Mazur J, Kaderali L, Kaul A, Zeuge U, Windisch MP, Trippler M, Lohmann V, Binder M, Frese M, Bartenschlager R
(Siehe online unter https://doi.org/10.1002/hep.25908) - 2012. Persistence of HCV in quiescent hepatic cells under conditions of an interferon-induced antiviral response. Gastroenterology. 143(2):429-38.e8
Bauhofer O, Ruggieri A, Schmid B, Schirmacher P, Bartenschlager R
(Siehe online unter https://doi.org/10.1053/j.gastro.2012.04.018) - 2013. Factors that determine the antiviral efficacy of HCV-specific CD8(+) T cells ex vivo. Gastroenterology. 144(2):426-36
Seigel B, Bengsch B, Lohmann V, Bartenschlager R, Blum HE, Thimme R
(Siehe online unter https://doi.org/10.1053/j.gastro.2012.10.047) - 2014. Inhibition of HCV replication by cyclophilin antagonists is linked to replication fitness and occurs by inhibition of membranous web formation. Gastroenterology. 146(5):1361-72
Madan V, Paul D, Lohmann V, Bartenschlager R
(Siehe online unter https://doi.org/10.1053/j.gastro.2014.01.055) - 2015. Activation of Type I and III Interferon Response by Mitochondrial and Peroxisomal MAVS and Inhibition by Hepatitis C Virus. PLoS Pathog. 11(11):e1005264. eCollection 2015 Nov.
Bender S, Reuter A, Eberle F, Einhorn E, Binder M, Bartenschlager R
(Siehe online unter https://doi.org/10.1371/journal.ppat.1005264) - 2015. Control of temporal activation of hepatitis C virus-induced interferon response by domain 2 of nonstructural protein 5A. J Hepatol. 63(4):829-37
Hiet MS, Bauhofer O, Zayas M, Roth H, Tanaka Y, Schirmacher P, Willemsen J, Grünvogel O, Bender S, Binder M, Lohmann V, Lotteau V, Ruggieri A, Bartenschlager R
(Siehe online unter https://doi.org/10.1016/j.jhep.2015.04.015) - 2015. Type I and type II interferon responses in two human liver cell lines (Huh-7 and HuH6). Genom Data. 7:166-70
Grünvogel O, Esser-Nobis K, Windisch MP, Frese M, Trippler M, Bartenschlager R, Lohmann V, Binder M
(Siehe online unter https://doi.org/10.1016/j.gdata.2015.12.017) - 2016. A Slow Maturation Process Renders Hepatitis B Virus Infectious. Cell Host Microbe. 20(1):25-35
Seitz S, Iancu C, Volz T, Mier W, Dandri M, Urban S, Bartenschlager R
(Siehe online unter https://doi.org/10.1016/j.chom.2016.05.013) - 2016. Evidence that hepatitis B virus replication in mouse cells is limited by the lack of a host cell dependency factor. J Hepatol. 64(3):556-64
Lempp FA, Mutz P, Lipps C, Wirth D, Bartenschlager R, Urban S
(Siehe online unter https://doi.org/10.1016/j.jhep.2015.10.030)
