Hepatitis B virus covalently closed circular DNA establishment (HBV cccDNA establishment)

Hepatitis B virus covalently closed circular DNA (cccDNA) establishment refers to the intracellular process by which the viral relaxed circular (rc) DNA genome is converted into a stable episomal cccDNA form within the nucleus of infected hepatocytes. This minichromosome serves as the transcriptional template for all HBV RNAs and is responsible for the persistence of infection and resistance to current antiviral treatments[1][2][3][4][5][6]. Formation involves the repair of rcDNA utilizing host DNA repair machinery, with key human factors such as proliferating cell nuclear antigen (PCNA), replication factor C (RFC), DNA polymerase delta (POLδ), flap endonuclease 1 (FEN-1), and DNA ligase 1 (LIG1) being essential for this process[3]. The persistent presence of cccDNA enables ongoing production of viral proteins and new virions, playing a central role in chronic hepatitis B infection and the development of hepatocellular carcinoma[5][6]. Current therapies suppress viral replication but do not eradicate cccDNA, making its establishment and maintenance a crucial therapeutic target[5][6]. The target “Hepatitis B virus cccDNA establishment” is not a single molecule but rather a process or molecular event critical for HBV persistence[1][2][3][4][5][6]. The term is imprecise as a strict “target”; it more accurately refers to the process leading to the formation of HBV cccDNA, which itself is a molecular entity and the target of research and future direct-acting therapies (hence is_incorrect: true). Targeting cccDNA establishment remains a key unmet goal for curative therapies in hepatitis B.

Other names

Hepatitis B virus cccDNA formationHBV cccDNA generationcccDNA establishmentCovalently closed circular DNA formation

No approved therapy directly eliminates cccDNA; nucleos(t)ide analogs inhibit replication but cccDNA persists[6][5]