使用SMC5 / 6沉默HBV转录：是否找到路径？

StephenW

Silencing HBV transcription with SMC5/6: has a path been found?

    http://orcid.org/0000-0002-8711-4240John Tavis, http://orcid.org/0000-0003-1682-0460Ranjit Chauhan

    Correspondence to Dr John Tavis, Molecular Microbiology and Immunology, Saint Louis University, Saint Louis, MO 63104, USA; [email protected]

http://dx.doi.org/10.1136/gutjnl-2021-324144

    Linked ArticlesRequest Permissions

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.

StephenW

使用SMC5 / 6沉默HBV转录：是否找到路径？

    http://orcid.org/0000-0002-8711-4240John Tavis，http：//orcid.org/0000-0003-1682-0460Ranjit Chauhan

    美国圣路易斯大学分子生物学和免疫学John Tavis博士，密苏里州63104； [email protected]

http://dx.doi.org/10.1136/gutjnl-2021-324144

    链接的文章请求权限

慢性乙型肝炎病毒（HBV）感染是通过病毒核共价闭合环状DNA（cccDNA）来维持的，ccDNA是HBV mRNA的转录模板。 cccDNA在目前的治疗方法中是持久的，但对HBV感染的功能性治疗要求停止治疗后体内残留的任何cccDNA的稳定，非治疗性沉默。1cccDNA在感染过程中通过结合染色体的结构维持而自然沉默。 5/6（SMC5 / 6）与cccDNA形成复合物，而HBV则通过与SMC5 / 6结合并触发其蛋白酶体降解的HBx蛋白来拮抗这种沉默。2在肠道中，Allweiss和Giersch等[3]研究了HBV mRNA转录会发生什么。抑制携带人源化肝脏的HBV感染的嵌合小鼠中病毒mRNA和抗原水平的抑制期间和之后。用小干扰RNA（siRNA）或聚乙二醇化干扰素α（Peg-IFNα）抑制所有HBV mRNA，可增加SMC5 / 6与cccDNA的结合，抑制HBV转录并降低HBV蛋白的产生。 siRNA和Peg-IFNα的撤回导致SMC5 / 6降解以及病毒转录和蛋白质水平反弹。最后，在终止siRNA或Peg-IFNα治疗后，用有效的HBV进入抑制剂myrcludex B（bulevirtide，Hepcludex）治疗小鼠，可大大提高SMC5 / 6介导的转录抑制的持久性。