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). HBV and HCV can both cause persistent infections of the liver. More than 500 million people worldwide are persistently infected with either of these two viruses (350 to 400 million in case of HBV; 170 million in case of HCV) thus presenting a major global health problem. In Germany about 400,000 to 500,000 people are chronically infected either with HBV or HCV. These people are at high risk to develop serious liver damage including liver cirrhosis and hepatocellular carcinoma (HCC). According to the statistics of the Robert Koch Institute, 57% of all cases of liver cirrhosis and 78 % of all HCC cases worldwide are linked to HBV or HCV infection.

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 FOR aims to utilize novel and highly efficient cell culture systems to study the mechanisms of persistence underlying HBV and HCV infections as well as HBV-HCV coinfections.

Most importantly, these cell culture systems allow for the first time the detailed analysis of the strategies of viral persistence both at the level of innate and adaptive immune response. The collection of the newly generated cell culture systems supporting HBV, HCV and HBV-HCV infection and replication is unique and provides the experimental platform for the proposed project of this FOR. 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. Viral and cellular factors of persistence. Viral and host cell factors playing a key role in the generation and maintenance of the reservoirs of persistence of HBV and HCV will be analyzed.
2. Role of the innate immunity. The main focus will be on type 1 interferon (IFN) and the mechanisms by which HCV and HBV can persist in the face of an IFN-induced antiviral status.
3. Role of the acquired immunity. The FOR will examine the mechanisms responsible for T-cell mediated inhibition of HBV and HCV replication, for the elimination of infected cells and for T-cell failure. Owing to the focus of the FOR, primarily CD8+ T-cell effector functions as well as the priming of virus specific T-cells will be analyzed.