FOR 1202:  Mechanisms of Persistence of Hepatotropic Viruses

• Subject Area: Medicine
• Term: from 2009 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 99161398

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections belong to the most frequent infectious diseases. About 600 million people worldwide are persistently infected with either of these two viruses and these people have a high risk to develop serious liver diseases. In fact, persistently HBV-infected individuals have an about 100-fold higher risk to develop liver cirrhosis or hepatocellular carcinoma (HCC) as compared to healthy individuals and up to 25 percent of virus carriers may die due to virus-associated liver failure. In case of HCV it is estimated that about 3-20 percent of chronically infected patients develop liver cirrhosis and within cases of HBV-HCV coinfection, the course of disease is even more serious and coinfected individuals more often develop liver cirrhosis and HCC as compared to monoinfections.
The central aim of this Research Unit is to unravel in molecular detail the viral and immunological mechanisms leading to persistence caused by the two medically most relevant hepatitis viruses, HBV and HCV. Up to now in vivo analyses of HBV and HCV infections are not possible due to the lack of immune competent animal models (besides chimpanzees) in which persistent infections can be established.
To account for these circumstances, this Research Unit aims to utilise novel and highly efficient cell culture systems to study the molecular mechanisms of persistence underlying HBV and HCV infections as well as HBV-HCV coinfections. The basic principles of these systems that support the complete replication cycle of both viruses have already been established by the eight members of the Research Unit from Heidelberg and Freiburg, in part by close collaboration between some of the participating members of the Research Unit. Most importantly, these cell culture systems allow the detailed analysis of the strategies of viral persistence under well-defined laboratory conditions.
Taking advantage of these newly developed tools, strategies of HBV and HCV persistence will be addressed at three complementary and thematically inter-linked levels: (1) the viral and cellular factors of persistence, (2) the role of the innate immunity with a main focus on type 1 interferon, (3) the role of the acquired immunity for inhibition of viral replication and for elimination of infected cells.

• DFG Programme: Research Units
• International Connection: Switzerland

Projects

• Addressing the multi-factorial impact on viral persistence by integrative dynamic pathway modeling (Applicants Klingmüller, Ursula ;  Timmer, Jens )
• Cellular DNA repair in cccDNA formation during hepatitits B virus infection - addressing functionally redundant repair pathways (Applicant Nassal, Michael )
• Central coordination of the research unit 1202 (Applicant Bartenschlager, Ralf Friedrich Wilhelm )
• Immunopathogenesis of hepatitis B virus and hepatitis C virus infection (Applicant Thimme, Robert )
• Impact of HBV-HCV coinfection on virus-specific cytotoxic T-cell responses and viral persistence (Applicant Brass, Volker )
• Mechanisms of Hepatitis B virus X-protein (HBx)- and interferon (IFN)-mediated regulation of viral transcription in authentic cell culture systems (Applicant Urban, Stephan )
• Mechanisms of immune evasion by hepatitis C virus and their role in establishment of viral persistence (Applicant Lohmann, Volker )
• Protective CD8+ T cell responses and role of viral escape in HBV infection (Applicant Neumann-Haefelin, Christoph )
• Virological and immunological mechanisms of hepatitis C virus persistence (Applicant Bartenschlager, Ralf Friedrich Wilhelm )

• Spokesperson: Professor Dr. Ralf Friedrich Wilhelm Bartenschlager