B Testoni & F Zoulim’s group

Project :

Biology of cccDNA and novel biomarkers for in chronic HBV infections

Context: The goals of current HBV therapy are to prevent the development of cirrhosis, hepatic decompensation, hepatocellular carcinoma (HCC) and death from HBV-related liver disease, which represents the 3^rd mortality cause worldwide. This, associated to suboptimal vaccination coverage in highly endemic areas, make CHB a worldwide major health burden, with more than 240 million people being chronic carriers of the infection.

Current first-choice treatments for chronic hepatitis B (CHB) are able to efficiently induce viral suppression in the majority of patients, but life-long therapy is needed to maintain infection under control due to their inability to eliminate the virus from infected hepatocytes. Indeed, the hepatitis B virus (HBV) minichromosome, the so-called covalently closed circular (ccc)DNA, is wrapped around nucleosomes to form a stable, chromatinized structure that is regulated by epigenetic mechanisms and is responsible for viral persistence in the nucleus of infected cells. Moreover, the ability of HBV to integrate into the host genome hampers a complete sterilizing cure.

The residual viral replication and antigen production in most patients under treatment substantially contributes to the residual risk of hepatocarcinogenesis.

New therapeutic approaches are needed to overcome HBV persistence in the infected cells, or at least, to control its transcriptional and replicative activity.

Concomitantly, the advent of new combinatorial therapies requires the need of defining new endpoints for the assessment of therapeutic efficiency and of serum standardized assays representing surrogate markers intrahepatic viral activity.

Objectives:

1°) Generate new knowledge on cccDNA biology, in particular on the key steps leading to its formation and to its transcriptional regulation once the pool is established, in vitro and in vivo

2°) Investigate Gene editing approaches to induce cccDNA degradation

3°) Investigate new serum surrogate markers for intrahepatic cccDNA amount and/or activity; assess their correlation with intrahepatic HBV activity and evaluate their prognostic value in CHB patients cohorts

4°) Investigate the impact of viral/host genome genetic variability on cccDNA epigenetic regulation and on new antiviral treatments efficiency

5°) Analyze HBV integration in the host genome and its role in liver pathogenesis