Hepatitis B virus cccDNA: Formation, regulation and therapeutic potential

Hepatitis B virus (HBV) infection remains a major public health concern worldwide with about 257 million individuals chronically infected. Current therapies can effectively control HBV replication and slow down disease progress, but cannot cure HBV infection. Upon infection, HBV establishes a pool of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. The cccDNA exists as a minichromosome and resists to antivirals, thus a therapeutic eradication of cccDNA from the infected cells remains unattainable. In this review, we summarize the state of knowledge on the mechanisms underlying cccDNA formation and regulation, and discuss the possible strategies that may contribute to the eradication of HBV through targeting cccDNA. •HBV establishes a pool of covalently closed circular DNA (cccDNA) minichromosome in the nucleus of infected hepatocytes.•HBV cccDNA is responsible for viral persistence and resistance to current antiviral treatments.•The formation of cccDNA involves host DNA repair machinery.•HBV hijacks host ubiquitous and liver-enriched transcription factors for cccDNA transcriptional regulation.•Elimination or transcriptional silencing of cccDNA is essential for HBV cure.