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Hepatitis B virus (HBV) causes chronic infection in at least 250 million people worldwide, resulting in approximately 850 000 deaths annually. Chronic carriers are at risk of developing severe liver disease including decompensated cirrhosis and hepatocellular carcinoma (HCC). HBV infection can be prevented with a highly effective prophylactic vaccine. Viraemia can be suppressed with nucleos/tide analogues targeting the HBV polymerase, but standard-of-care therapy rarely leads to a cure leaving patients requiring lifelong therapy to prevent relapse of viral replication. Furthermore, even on treatment patients remain at a residual risk of developing HCC. Development of treatments resulting in a functional cure has been hampered by our incomplete understanding of HBV persistence and the difficulty of targeting pharmacologically essential steps in the viral replicative cycle.1
HBV is a partially double-stranded DNA virus of the Hepadnaviridae family, which has a complex replication cycle and is intricately intertwined with the host cell DNA repair machinery (figure 1). Following receptor-mediated endocytosis, hepatitis B virions carry a form of the genome into the host cell, the human hepatocyte, referred to as relaxed circular DNA (rcDNA). rcDNA is a lesion-bearing molecule, which must be repaired to form covalently closed circular DNA (cccDNA), the major template for HBV gene transcription, which is central to HBV persistence. HBV’s 3.2 kb genome only encodes four gene products, none of which can convert rcDNA into cccDNA and thus the virus relies on numerous host factors for completing this process, some identified in targeted loss-of-function and biochemical screens (figure 1). TDP2 plays a …
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BT and AP contributed equally.
Contributors Both authors contributed equally.
Funding National Institute of Allergy and Infectious Diseases (Grant number: R01AI138797, R01AI153236).
Competing interests BT receives funding from Hoffman La Roche, Assembly Biosciences and Beam Therapeutics; AP is founder of Acurasset Therapeutics and serves as a consultant for Lycia Therapeutics.
Provenance and peer review Commissioned; internally peer reviewed.