TRR 179:  Determinants and dynamics of elimination versus persistence of hepatitis virus infection

• Subject Area: Medicine
• Term: since 2016
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 272983813

Infections with hepatitis viruses are a major public health concern causing high morbidity and mortality worldwide. The underlying reasons are manifold like e.g. the high propensity to establish persistence, the high global prevalence of viral hepatitis and a high proportion of undiagnosed infections. The last few years have seen major developments in the field of viral hepatitis including cure of chronic hepatitis C and a new therapy for hepatitis D virus (HDV) infection with the entry inhibitor Hepcludex (Bulevirtide). Moreover, important aspects of the biology of enteric hepatitis viruses, i.e. hepatitis A virus (HAV) and hepatitis E virus (HEV), have been discovered. Infections with hepatitis viruses can be either acute self-limiting or persistent, depending on the virus and various so far poorly understood conditions that are governed by a complex interplay of host and viral factors. Deciphering the mechanisms and dynamics orchestrating this complex interplay is the central aim of TRR179. Required approaches take into account the tolerogenic liver microenvironment, the cross-talk between innate and adaptive immune responses, the duration of immune stimulation, the amount of viral antigen and the cell biology underlying the replication cycle of each hepatitis virus. Therefore, an integrative and highly interdisciplinary approach is required. Capitalizing on past achievements and including novel scientific discoveries and technologies, we will retain our main focus on the fundamental principles orchestrating hepatitis virus elimination versus persistence. These include novel therapeutic concepts towards cure of HBV and HDV infections, most notably highly promising results from combination therapies that include Bulevirtide and the development of a therapeutic HBV vaccine (TherVacB) that will enter a phase I clinical trial in Q1/2024. While keeping a strong emphasis on fundamental research in hepatitis virus persistence strategies, we will intensify our clinical and translational efforts to increase the currently unsatisfyingly low success rate of functional cure, both in HBV mono- and HBV/HDV co-infection. TRR179 provides the necessary framework to address the salient questions in the field and to conduct studies at the molecular and cellular level, translate obtained results into relevant preclinical in vivo systems and validate the findings in hepatitis virus-infected individuals. Although TRR179 focuses on hepatitis viruses, the basic principles and mechanisms uncovered here will likely be applicable to persistent infections by other pathogens.

• DFG Programme: CRC/Transregios

Current projects

• 01 - Fate and function of scarred virus-specific T cells in chronic viral hepatitis (Project Heads Hofmann, Maike ;  Thimme, Robert )
• 02 - Virus-specific CD8+ T cell responses in hepatitis B/D virus co-infection: mechanisms of failure and strategies for restoration (Project Heads Luxenburger, Hendrik ;  Neumann-Haefelin, Christoph )
• 04 - Regulation of virus-specific CD4 T helper cell responses in viral hepatitis (Project Head Böttler, Tobias )
• 05 - Reconstitution of potent antiviral CD8 T cell immunity to achieve elimination of infected hepatocytes during persistent HBV infection (Project Head Knolle, Percy Alexander )
• 07 - Dissecting NK cell-reactivity against hepatitis virus infection (Project Head Cerwenka, Adelheid )
• 09 - Control of hepatitis virus infection by the interferon system and by exploiting virus – host cell interactions (Project Head Bartenschlager, Ralf Friedrich Wilhelm )
• 11 - Effects of constitutive cytokine signalling on tissue homeostasis and liver cell-intrinsic responsiveness to hepatitis virus infection (Project Heads Beisel, Claudia ;  Binder, Marco ;  Pichlmair, Andreas )
• 13 - Dynamics of anti-viral immunity against viral infection of the liver (Project Heads Ntziachristos, Vasilis ;  Wohlleber, Dirk )
• 14 - Establishment and Fate of HBV cccDNA (Project Heads Protzer, Ulrike ;  Wettengel, Jochen )
• 15 - Characterization of hepatitis D virus cell division-mediated spread and interference through innate and adaptive immune responses (Project Heads Nkongolo, Shirin ;  Urban, Stephan )
• 16 - Determinants, dynamics and diversity of SUMO/PML nuclear bodies in the control of hepatitis B virus infection and cccDNA (Project Heads Nassal, Michael ;  Schreiner, Sabrina )
• 17 - Contribution of innate immune responses to persistence versus clearance of hepatitis C and hepatitis A virus infections (Project Head Lohmann, Volker )
• 18 - Reconstitution of antiviral immunity and elimination of persisting hepatitis B virus infection (Project Heads Grimm, Dirk ;  Kosinska, Anna Dagmara ;  Protzer, Ulrike )
• 20 - Stem-like CD8+ T cells in chronic viral hepatitis: maintenance and targeting of CD8+ T cell immunity (Project Head Hofmann, Maike )
• 21 - Metabolic regulation of the virus-specific T cell response in viral hepatitis (Project Head Bengsch, Ph.D., Bertram )
• 22 - From genotype to phenotype: Towards a better understanding of hepatitis E virus tropism and chronic infection (Project Heads Boulant, Steeve ;  Dao Thi, Ph.D., Viet Loan )
• 23 - The dynamics of hepatitis B virus morphogenesis and its relevance to persistent infection. (Project Heads Schütz, Anne ;  Seitz, Ph.D., Stefan )
• 24 - Functional analysis of molecular perturbations induced by Hepatitis B and D virus infection (Project Head Pichlmair, Andreas )
• 25 - Metabolic regulation of mucosal-associated invariant T (MAIT) cell anti-viral function against hepatitis B virus infection (Project Head Böttcher, Ph.D., Katrin )
• MGK19 - Integrated Research Training Group “Immunovirology” (Project Heads Bauer, Tanja ;  Böttcher, Ph.D., Katrin ;  Hengel, Hartmut ;  Lohmann, Volker ;  Ruggieri, Ph.D., Alessia ;  Schreiner, Sabrina )
• Z01 - Central tasks of the transregional collaborative research centre 179 (Project Head Bartenschlager, Ralf Friedrich Wilhelm )
• Z02 - High-resolution multiparametric cell and tissue analysis & establishment of a spatially resolved cell atlas of the chronically hepatitis B virus infected liver (Project Heads Andrä, Immanuel Anton ;  Bauer, Tanja ;  Bengsch, Ph.D., Bertram ;  Eils, Roland ;  Mogler, Carolin ;  Neumann-Haefelin, Christoph ;  Schiemann, Matthias )
• Z03 - Experimental and computational single-cell analysis with high spatial resolution (Project Heads Herrmann, Carl ;  Rippe, Karsten )

Completed projects

• 03 - Generation of effective antiviral CD4 T cell immunity in viral hepatitis and its association to unique signatures of transcription factors (Project Head Raziorrouh, Bijan )
• 06 - Role of platelets in control and clearance of hepatitis B virus infection via modulation of liver tissue environment and metabolism (Project Head Heikenwälder, Mathias )
• 08 - Mechanisms of interferon induction by hepatitis D virus and impact of chronic innate immune activation on antiviral immunity (Project Heads Bohne, Felix Mark ;  Hornung, Veit ;  Knolle, Percy Alexander )
• 10 - Identification of systems properties determining the dynamics of the hepatitis B virus infection cycle and cross-talk to host cell responses (Project Heads Klingmüller, Ursula ;  Timmer, Jens )
• 12 - Role of the host stress response in the establishment of viral persistence: comparative analysis of hepatitis C virus and hepatitis A virus infection (Project Head Ruggieri, Ph.D., Alessia )

• Applicant Institution: Ruprecht-Karls-Universität Heidelberg
• Co-Applicant Institution: Albert-Ludwigs-Universität Freiburg; Technische Universität München (TUM)
• Participating Institution: Ludwig-Maximilians-Universität München; Fakultät für Chemie und Pharmazie; Department Chemie; Deutsches Krebsforschungszentrum (DKFZ); Helmholtz Zentrum München; Deutsches Forschungszentrum für Gesundheit und Umwelt
• Participating University: Ludwig-Maximilians-Universität München
• Spokesperson: Professor Dr. Ralf Friedrich Wilhelm Bartenschlager