Host factors in hepatitis B virus cccDNA formation as novel antiviral targets and biomarkers - identification, preclinical evaluation and impact for liver disease. – hepBccc

Chronic hepatitis B (CHB), caused by hepatitis B virus (HBV), is a leading cause of liver cirrhosis, liver failure and hepatocellular carcinoma (HCC). Of the 350 million chronic HBV carriers worldwide ~20% will die from terminal liver disease. 14 million Europeans live with CHB; the associated mortality rate is ~36,000 deaths/year. Current treatments offer at best control of infection but no cure. Chronicity relies on a unique intracellular viral replication intermediate termed covalently closed circular (ccc) DNA which ensures progeny virus production; its eradication is the prerequisite for a cure. However, how cccDNA is generated from the relaxed circular (RC) DNA genome present in infectious virions is not known, except that the multiple conversion steps required must largely depend on host factors. To identify such host factors as novel antiviral targets, this proposal combines the complementary competences of four HBV-experienced partner labs (Baumert & Brino, France; Bielawski, Poland; Nassal, Germany) using state-of-the-art technologies and most recent virological advances/findings. These include RNAi-based screening and preclinical validation of targets by advanced cell-culture systems, including HBV-infectable
cell lines and novel HBV reporter vectors. HBV-relevant host factors will be explored as antiviral targets. For most rapid translation into the clinic, a lab renowned for development of antivirals (Neyts & Dallmeier, Leuven, Belgium) will join as non-funded associate partner to initiate HTS screening for
small-compound host factor inhibitors. Target discovery will be complemented by identification of pertinent viral and host factor polymorphisms in clinical HBV patient sample repositories (Baumert & Bielewski), using advanced mass spectrometry (MS). Patient-specific polymorphisms plus clinical data will
be merged into a correlative virus/host factor/disease data base to reveal novel biomarkers for progression of liver disease and personalized treatment approaches. To help exploit project-specific R&D results, the partner SME VIRONEXX (Strasbourg, F) will professionally assess market potential via
established contacts with major pharma; this feedback will help early-on to focus the program on targets with the highest foreseeable impact for biomarker and drug development. We expect this project to substantially advance basic knowledge of a key issue in HBV pathogenicity and allow identification of new targets that are crucial for the eventual cure of chronic hepatitis B. Moreover, the project contributes to developing and jointly using EU-wide data bases and technology platforms.