Hepatitis B virus (HBV) infection is a major global public health problem. Effective prophylaxis by vaccination is
available for more than 20 years. Despite this, chronic hepatitis B is still an incurable disease. The infection is characterized by acute hepatitis, frequently leading to symptomless chronicity, with the risk of slowly progressing to
cirrhosis and hepatocellular carcinoma (HCC) of which HBV is the main cause (> 70%). HBV DNA is protected by a protein capsid made up of the core protein (HBc). HBc, apart from its role in the formation of capsids, is involved in various stages of the viral replication such as the reverse transcription of the pregenomic RNA into DNA or the nuclear import of the viral DNA. HBc is also recruited onto the viral nuclear DNA (cccDNA) and modifies its structure. Hbc may also be involved in transcriptional regulation of HBV and cellular genes. HBc contains a PDZ domain recognition motif (called PBM for PDZ-binding motif) exposed at the C-terminus of its sequence. These PBM motifs interact with a large family of protein-protein interaction domains called PDZ (PSD-95 / Dlg/ ZO-1) which are involved in many human signaling pathways. Very little is known about the HBc targets containing PDZ domains in the infected cell. We identified potential new cellular partners of HBc through PDZ-PBM interactions by screening the HBc PBM against a full library of human PDZ domains. We will select proteins with PDZ domains relevant for viral replication. We will validate their role in different cell models and identify the stage of the viral cycle they affect. We will characterize the functional and structural properties of the viral HBc protein in interaction with the PDZ proteins selected for their impact on the viral life cycle, using a combined approach of integrative structural biology and biophysics. The identification of cellular proteins involved in the activities of HBc, and the structural characterization of their interactions will open up new avenues of research on the pathophysiology of HBV and could lead to the identification of new therapeutic targets in the treatment of chronic hepatitis B.