Hepatitis B virus covalently closed circular DNA and integrated hepatitis B virus DNA (HBV cccDNA and integrated HBV DNA)

Hepatitis B virus covalently closed circular DNA (cccDNA) is a unique, episomal viral DNA molecule formed in the nucleus of infected hepatocytes from relaxed circular DNA (rcDNA) delivered by incoming virions. cccDNA is organized into a chromatin-like minichromosome, associating with histones (H2A, H2B, H3, H4, H1) and non-histone proteins such as HBc and HBx. It serves as the template for all HBV mRNAs, enabling persistent viral replication and chronic infection. Current therapies, including nucleos(t)ide analogs, suppress viral polymerase activity and replication but do not eliminate cccDNA. This durability underlies the difficulty in curing hepatitis B and remains a global health challenge. Integrated HBV DNA refers to viral DNA fragments stably incorporated into the host hepatocyte genome, which occurs via illegitimate integration events. Integrated HBV DNA can disrupt host gene function and promotes the development of hepatocellular carcinoma (HCC). Both cccDNA and integrated HBV DNA are recognized as key molecular targets for curative and preventative strategies, but as of 2024, there are no approved drugs that directly eliminate either form.

Other names

cccDNAintegrated HBV DNAHBV episomeHBV chromosomal integrationHBV minichromosomeHBV covalently closed circular DNA

Inhibition of HBV polymerase/viral replication (current nucleos(t)ide analogs; suppress cccDNA transcription) Direct cleavage/inactivation of cccDNA (gene editing—experimental) Silencing of cccDNA minichromosome via epigenetic modifiers (experimental)