FOR 1202: Mechanisms of Persistence of Hepatotropic Viruses
Final Report Abstract
Persistent infections with hepatotropic viruses are still major risk factors for chronic liver diseases. Worldwide, about 350 million people are persistently infected with the hepatitis B virus (HBV) and ~170 million with the hepatitis C virus (HCV). In addition, co-infections with HBV and hepatitis D virus (HDV) or HBV and HCV are frequent and they dramatically accelerate and worsen the course of disease. 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 were the focus of both funding periods of the research group (FOR) 1202 “Mechanisms of persistence of hepatotropic viruses”. In both funding periods the FOR1202 aimed to decipher the immunological and virological factors governing persistence. One central achievement made was 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. By making further refinements of these cell culture models, some of which have now become state-of-the-art in the field (e.g. the T cell co-culture system) and by studying central questions related to persistence the FOR1202 substantially contributed to the advancement of our understanding of mechanisms of persistence. By focussing on viral and cellular factors of persistence major contributions were made with respect to the covalently closed circular (ccc)DNA as HBV persistence reservoir. In addition several players in establishing HCV persistence were identified. The role of the innate immune response in establishing persistence was also intensively investigated by the FOR1202. Finally, the role of the adaptive immune response in establishing persistence was one of the central focuses during both funding periods. Major contributions were made in characterizing HCV- and HBV-specific T cell epitopes and their role in immune escape and elimination of viral infection. All these findings were the basis for the successful application of the TRR179 (Determinants and dynamics of elimination versus persistence of hepatitis virus infection) which was started in July 2016.
