Recombinant covalently closed circular DNA of hepatitis B virus induces long-term viral persistence with chronic hepatitis in a mouse model
Recombinant covalently closed circular DNA of hepatitis B virus induces long-term viral persistence with chronic hepatitis in a mouse model
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乙型肝炎病毒的重组共价闭合环状 DNA 在小鼠模型中诱导慢性肝炎的长期病毒持续存在
DOI：
10.1002/hep.29406
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发表时间：
2018-01-01
期刊：
影响因子：
13.5
通讯作者：
Deng, Qiang
中科院分区：
文献类型：
--
作者：
Li, Gaiyun;Zhu, Yuanfei;Deng, Qiang
乙型肝炎病毒 (HBV) 的共价闭合环状 DNA 对于病毒在体内的持续存在至关重要。我们最近报道了一种通过位点特异性 DNA 重组重组 HBV 共价闭合环状 DNA (rcccDNA) 的技术。使用水动力注射，rcccDNA 在免疫功能正常的小鼠中诱导暂时延长的 HBV 抗原血症，类似于急性缓解 HBV 感染。在这项研究中，我们模拟了慢性肝炎的病理生理学影响，以在小鼠模型中重现 rcccDNA 持久性。我们发现，在免疫反应受损或转录活性受到抑制的情况下，rcccDNA 能够实现持久的持久性。为了密切模拟慢性肝炎，我们使用复制缺陷型重组腺病毒载体将 rcccDNA 递送至肝脏，这导致在白蛋白启动子下表达 Cre 重组酶的转基因小鼠中，在整个实验期间（> 62 周）中 HBV 持续存在。在小鼠肝脏中发现了持续的坏死性炎症反应和纤维化，在病毒持续存在的晚期阶段常见不典型增生病变，类似于临床慢性肝炎的进行性病理学。结论：rcccDNA在体内本质上稳定，能够在慢性肝炎的情况下长期持续存在，而病毒的持续存在反过来可能促进慢性肝病的进展；我们的研究还提出了小鼠体内 HBV cccDNA 持久性的替代模型，可以增进我们对慢性乙型肝炎发病机制的理解。 (Hepatology 2018;67:56-70)。
Covalently closed circular DNA of hepatitis B virus (HBV) is critical for viral persistence in vivo. We recently reported a technique involving recombinant covalently closed circular DNA (rcccDNA) of HBV by site-specific DNA recombination. Using hydrodynamic injection, rcccDNA induces a temporarily prolonged HBV antigenemia in immunocompetent mice, similar to acute resolving HBV infection. In this study, we simulated the pathophysiological impact of chronic hepatitis to reproduce rcccDNA persistence in mouse models. We showed that rcccDNA achieved long-lasting persistence in the presence of a compromised immune response or when transcriptional activity was repressed. To closely mimic chronic hepatitis, we used a replication-defective recombinant adenoviral vector to deliver rcccDNA to the liver, which led to prominent HBV persistence throughout the experiment duration (>62 weeks) in transgenic mice expressing Cre recombinase under the albumin promoter. A sustained necroinflammatory response and fibrosis were identified in mouse livers, with dysplastic lesions commonly seen during the late stage of viral persistence, analogous to the progressive pathology of clinical chronic hepatitis. Conclusion: rcccDNA was intrinsically stable in vivo, enabling long-term persistence in the context of chronic hepatitis, and viral persistence, in turn, may promote progression of chronic liver disease; our study also presented a surrogate model of HBV cccDNA persistence in mice that could advance our understanding of the pathogenesis of chronic hepatitis B. (Hepatology 2018;67:56-70).