Aims and Objectives

The central aim of this research unit (FOR) is to unravel in molecular detail the viral and immunological mechanisms leading to persistence caused by the two medically most relevant hepatitis viruses, hepatitis B virus (HBV) and hepatitis C virus (HCV).

Persistent infections with hepatotropic viruses are major risk factors for chronic liver diseases. Worldwide, about 350 million people are persistently infected with HBV and ~170 million with HCV. Although acute infections with these viruses in the majority of cases are asymptomatic or associated with rather mild symptoms, the clinical challenge of infections especially with HBV and 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.

In the light of the high medical relevance, persistent infections especially with HBV and HCV are the focus of FOR1202. In the absence of robust immuno-competent animal models for HBV and HCV, studies conducted within FOR1202 focus on the development and use of cell culture models mimicking the in vivo situation as closely as possible. These systems support the complete HBV and HCV replication cycles, mimic persistent infection and allow studies of innate immune reactions as well as CD8+ T cell responses.

During the second funding period (October 2012 – September 2015) we have expanded the scope of FOR1202 by including a systems biology project. This project integrates various activities within FOR1202 that are related to the complexity of overlapping and redundant signalling pathways triggering an innate immune response. Taking advantage of the newly developed tools and based on the knowledge gained during the last funding period, strategies of HBV and HCV persistence will be addressed at three complementary and thematically inter-linked levels:

  1. Viral and cellular factors of persistence:
    Here we focus on viral and cellular proteins that play key roles in establishing and sustaining viral reservoirs of persistence. In case of HBV this relates to HBx and DNA repair enzymes responsible for formation, maintenance and transcriptional regulation of the cccDNA, the persistence reservoir of HBV. In case of HCV, we will study, amongst others, the role of HCV proteins in counteracting the induction of the interferon (IFN) system.
  2. Role of the innate immune response in establishing persistence:
    In this research area we will take advantage of the long-term live cell imaging systems established during the last funding period, to study the dynamics of the IFN response and its impact on HCV spread. We will develop mathematical models of the dynamic interplay of the host immune response and HCV and study innate signalling pathways triggered by infection or counteracted by viral proteins. Finally, we are using a systems approach to decipher the molecular mechanisms governing host cell responses resulting from cell exposure to multiple extra-cellular cues.
  3. Role of the adaptive immune response in establishing persistence:
    Studies in this research area relate to the molecular mechanisms of success or failure of T cells to control HBV and HCV infection. The cross-talk between pathogen-induced innate cytokines and the adaptive immune response against HBV and HCV is an important aspect that has been integrated into the research program of FOR1202.

© Dep. of Infectious Diseases, Molecular Virology. University of Heidelberg
Activation of Type I and III Interferon Response by Mitochondrial and Peroxisomal MAVS and Inhibition by Hepatitis C Virus.Bender S, Reuter A, Eberle F, Einhorn E, Binder M, Bartenschlager R. PLoS Pathog. 2015 Nov 20;11(11):e1005264.

Virus-specific CD4+ T Cells Have Functional and Phenotypic Characteristics of Follicular T-helper Cells in Patients With Acute and Chronic HCV Infections. Raziorrouh B, Sacher K, Tawar RG, Emmerich F, Neumann-Haefelin C, Baumert TF, Thimme R, Boettler T. Gastroenterology. 2015 Nov 13. pii: S0016-5085(15)01622-4.

Evidence that hepatitis B virus replication in mouse cells is limited by the lack of a host cell dependency factor. Lempp FA, Mutz P, Lipps C, Wirth D, Bartenschlager R, Urban S. J Hepatol. 2015 Nov 11. pii: S0168-8278(15)00736-9. doi: 10.1016/j.jhep.2015.10.030. [Epub ahead of print]