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Silencing HBV transcription with SMC5/6: has a path been found?
  1. John Tavis,
  2. Ranjit Chauhan
  1. Molecular Microbiology and Immunology, Saint Louis University, Saint Louis, Missouri, USA
  1. Correspondence to Dr John Tavis, Molecular Microbiology and Immunology, Saint Louis University, Saint Louis, MO 63104, USA; john.tavis{at}health.slu.edu

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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 al3 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 a …

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Footnotes

  • 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.

  • Patient consent for publication Not required.

  • Provenance and peer review Commissioned; internally peer reviewed.

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