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

Hepatitis B virus covalently closed circular DNA (cccDNA) and integrated HBV DNA are the primary molecular reservoirs responsible for the persistence of chronic hepatitis B (CHB) infection. cccDNA exists as a stable, chromatinized episome in the nucleus of infected hepatocytes, functioning as the essential transcriptional template for all viral RNAs, including the pregenomic RNA (pgRNA) necessary for viral replication (Seeger & Mason, 2015, Virology). Integrated HBV DNA occurs when viral sequences are incorporated into the host genome; although it cannot support full replication, it is a major source of Hepatitis B surface antigen (HBsAg) and contributes significantly to genomic instability and the development of hepatocellular carcinoma (Tu et al., 2017, Molecular Carcinogenesis). Current nucleos(t)ide analogue therapies suppress viral replication by inhibiting reverse transcription but fail to eliminate these DNA reservoirs, leading to viral rebound if treatment is discontinued (EASL, 2017, Journal of Hepatology). Novel therapeutic approaches, such as CRISPR/Cas9 gene editing and RNA interference (RNAi), are being developed to directly degrade or silence these DNA forms and their transcripts to achieve a functional cure (Martinez et al., 2021, Viruses). Targeting these reservoirs is critical for preventing long-term complications like cirrhosis and liver cancer (Revill et al., 2019, The Lancet Gastroenterology & Hepatology).

Other names

HBV cccDNAHBV episomeHBV minichromosomeIntegrated Hepatitis B virus DNAHBV DNA reservoir

Direct degradation of viral DNA via site-specific nucleases, epigenetic silencing of the cccDNA minichromosome, and RNA interference-mediated knockdown of transcripts derived from both cccDNA and integrated DNA templates (Martinez et al., 2021, Viruses; Wooddell et al., 2017, Science Translational Medicine).