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Chronic hepatitis B virus (HBV) infection is maintained by the viral nuclear covalently closed circular DNA (cccDNA) that is the transcriptional template for HBV’s mRNAs. The cccDNA is durable during current therapies, but a functional cure for HBV infections will require stable, off-treatment silencing of any cccDNA remaining in the body after treatment cessation.1 The cccDNA is silenced naturally during infection by binding of the structural maintenance of chromosome 5/6 (SMC5/6) complex to the cccDNA, and HBV antagonises this silencing with the HBx protein that binds to SMC5/6 and triggers its proteasomal degradation.2 In Gut, Allweiss and Giersch et al 3 explored what happens to HBV mRNA transcription during and after suppression of viral mRNA and antigen levels in HBV-infected chimeric mice carrying humanised livers. Suppressing all HBV mRNAs with a small interfering RNA (siRNA) or with pegylated interferon α (Peg-IFNα) increased SMC5/6 binding to the cccDNA, suppressed HBV transcription and reduced HBV protein production. Withdrawal of siRNA and Peg-IFNα led to degradation of SMC5/6 and rebound of viral transcription and protein levels. Finally, treating the mice with the potent HBV entry inhibitor myrcludex B (bulevirtide, Hepcludex) after cessation of siRNA or Peg-IFNα treatment greatly increased durability of SMC5/6-mediated transcriptional repression. This is …
Contributors Both authors wrote the manuscript jointly.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.
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