HBV over time: characteristics of viral pathogenesis in different phases of HBV-related disease

• Applicants: Professor Dr. Eberhard Hildt; Dr. Kai-Henrik Peiffer
• Subject Area: Virology
• Term: since 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 322274963

Chronic infection with hepatitis B virus (HBV) is common and is associated with a high risk for development of progressive liver disease. The course of disease is highly variable in chronic infected patients. Four phases of active clinical disease can be differentiated, depending on presence of HBeAg and hepatic inflammation. In order to better understand the underlying viral pathogenesis and to identify new prognostic biomarkers, the applicants performed many analyses within the DFG-project (sign removed) and (sign removed). Here, the viral genotype was identified as a major factor, which impacts the quantity and composition of released HBsAg and the morphology of released subviral particles (SVPs) in HBV positive inactive carriers. In contrast, no major genotype-specific differences regarding SVP morphology were observed in vitro in the analysis of HBeAg positive HBV expressing cells. In this follow-up project the impact of the clinical phase on morphogenesis of viral and subviral particles will be analyzed in detail. As the viral genotype was identified as a multifarious influencing factor on HBV virology the prevalence of coinfections of different genotypes within the same quasispecies and their relevance for virus-associated pathophysiology will be evaluated.Furthermore, it was noticed in the previous project that by using the example of viral genomes with preS mutations, HBsAg can also be sufficiently synthesized from in the human genome integrated viral sequences in HBeAg negative inactive carriers. In the follow-up project it will be analyzed which factors (i.e. viral genotype/ activity of the ROS system) determine viral integration in the human genome. In addition, it is planned to investigate if HBsAg synthesis from integrates plays a role for the morphogenesis of viral and subviral particles especially in case of coinfections with different intact genomes. In the previous project a certain polymorphism in the core promoter/HBx gene was identified in the cohort of HBeAg native inactive carriers, which was not detected in patients with HBV-associated liver cirrhosis. Therefore this polymorphism might act as a potentially prognostic marker. In the follow-up project further patient cohorts will be screened for this polymorphism and it is planned to develop a clinically feasible test-system. Furthermore, the impact of this polymorphism on HBV-mediated regulatory, fibrosis- and cancer-causing activity will be analyzed. On the one hand the results of this project will be relevant for the understanding of several aspects of the viral life circle and on the other hand the results might be important for the development of new antiviral strategies and prognostic markers

• DFG Programme: Research Grants
• International Connection: France, Italy
• Cooperation Partners: Professor Dr. Thomas Baumert; Professor Dr. Pietro Lampertico