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首页> 美国卫生研究院文献>Scientific Reports >Minicircle HBV cccDNA with a Gaussia luciferase reporter for investigating HBV cccDNA biology and developing cccDNA-targeting drugs
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Minicircle HBV cccDNA with a Gaussia luciferase reporter for investigating HBV cccDNA biology and developing cccDNA-targeting drugs

机译：带有Gaussia荧光素酶报道基因的HBV cccDNA小环用于研究HBV cccDNA生物学和开发靶向cccDNA的药物

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摘要

Chronic Hepatitis B Virus (HBV) infection is generally not curable with current anti-viral drugs. Virus rebounds after stopping treatment from the stable HBV covalently-closed-circular DNA (cccDNA). The development of drugs that directly target cccDNA is hampered by the lack of robust HBV cccDNA models. We report here a novel HBV cccDNA technology that will meet the need. We engineered a minicircle HBV cccDNA with a Gaussia Luciferase reporter (mcHBV-GLuc cccDNA), which serves as a surrogate to measure cccDNA activity. The mcHBV-GLuc cccDNA was easily produced in bacteria, and it formed minichromosomes as HBV cccDNA episome DNA does when it was transfected into human hepatocytes. Compared to non-HBV minicircle plasmids, mcHBV-GLuc cccDNA showed persistent HBV-GLuc activity and HBx-dependent gene expression. Importantly, the mcHBV-GLuc cccDNA showed resistance to interferons (IFN) treatment, indicating its unique similarity to HBV cccDNA that is usually resistant to long-term IFN treatment in chronic HBV patients. Most importantly, GLuc illuminates cccDNA as a surrogate of cccDNA activity, providing a very sensitive and quick method to detect trace amount of cccDNA. The mcHBV-GLuc cccDNA model is independent of HBV infection, and will be valuable for investigating HBV cccDNA biology and for developing cccDNA-targeting drugs.
机译：慢性乙型肝炎病毒（HBV）感染通常无法用当前的抗病毒药物治愈。停止治疗后，病毒从稳定的HBV共价闭合环状DNA（cccDNA）反弹。缺乏健壮的HBV cccDNA模型阻碍了直接靶向cccDNA的药物的开发。我们在这里报告了将满足需求的新型HBV cccDNA技术。我们用高斯荧光素酶报道基因（mcHBV-GLuc cccDNA）设计了一个微圆HBV cccDNA，它可作为替代物来测量cccDNA活性。 mcHBV-GLuc cccDNA很容易在细菌中产生，并且像转染到人肝细胞中的HBV cccDNA附加体DNA一样形成微染色体。与非HBV小环质粒相比，mcHBV-GLuc cccDNA显示出持久的HBV-GLuc活性和HBx依赖性基因表达。重要的是，mcHBV-GLuc cccDNA显示出对干扰素（IFN）治疗的抗性，表明其与HBV cccDNA的独特相似性，而后者通常对慢性HBV患者的长期IFN治疗具有抗性。最重要的是，GLuc将cccDNA阐明为cccDNA活性的替代品，为检测痕量cccDNA提供了一种非常灵敏且快速的方法。 mcHBV-GLuc cccDNA模型独立于HBV感染，对于研究HBV cccDNA生物学和开发靶向cccDNA的药物将具有重要的价值。

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