TRR179 – Determinants and dynamics of elimination versus persistence of hepatitis virus infection

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. In addition, members of TRR179 are at the scientific forefront of hepatitis virology and immunology and have demonstrated their strong expertise during the SARS-CoV-2 pandemic. By repurposing available Know-How and technologies and teaming up with colleagues from the clinic, biomedical research, diagnostics and vaccine development, TRR179 helped e.g. to decipher antiviral immune response against SARS-CoV-2, to unravel virus-host interactions of relevance to pathogenesis, to define the numbers of antigen contacts being required for optimal neutralization capacity, to establish and improve diagnostic assays and to develop antiviral drugs. In all these respects, TRR179 has demonstrated high innovation potential reaching far beyond viral hepatitis.