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Hépato-Gastro & Oncologie Digestive

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Molecular biology of hepatitis B virus covalently closed circular DNA (cccDNA): pathobiology and therapeutic impact Volume 19, issue 6, Juin 2012

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Authors
Inserm U1052, 151 Cours Albert Thomas, 69003 Lyon, France ; Hospices civils de Lyon, groupe hospitalier Nord, service d’hépatologie, Lyon, France ; Université Lyon I, Lyon, France

The replication of the hepatitis B virus (HBV) genome depends on a covalently closed circular DNA (cccDNA) which is the molecular form of viral persistence in the nucleus of infected hepatocytes. Viral cccDNA represent a viral “minichromosome” and serves as the template for viral transcription and replication. Host and viral factors contribute to the epigenetic regulation of the transcriptional activity of cccDNA. Current treatments do not affect specifically intrahepatic cccDNA and lead to slow kinetics of cccDNA clearance. In chronic hepatitis B (CHB), the amount of cccDNA and its transcriptional activity differ in the different stages of the natural history and are found higher in HBeAg positive- vs HBeAg negative- patients. Occult hepatitis B is associated with the persistence of cccDNA and the control of its transcriptional/replicative activity most likely by the host immune response. In case of loss of the immune control and HBs antibody, viral reactivation can occur from the pool of persisting cccDNA. Quantification of ccDNA is not easily performed in clinical practice. HBs antigen is expressed independently from viral replication per se and could serve as a surrogate marker for intrahepatic cccDNA. Recent studies suggest that the quantification of HBs antigen may be clinically relevant for the diagnosis of the different CHB stages or to monitor response to antiviral therapy. Because of the current lack of treatment specifically targeting cccDNA, a new goal of antiviral therapy could be the control of cccDNA activity and the subsequent HBs antigen seroconversion, which would allow treatment cessation.