Viral covalently closed circular DNA in a non-transgenic mouse model for chronic hepatitis B virus replication
Viral covalently closed circular DNA in a non-transgenic mouse model for chronic hepatitis B virus replication
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DOI：
10.1016/j.jhep.2005.07.030
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发表时间：
2006-02-01
影响因子：
25.7
通讯作者：
Hayashi, N
中科院分区：
文献类型：
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作者：
Takehara, T;Suzuki, T;Hayashi, N
背景/目的：缺乏支持慢性乙型肝炎病毒（HBV）感染的小动物模型阻碍了抗病毒药物在整个动物中的评估。虽然转基因小鼠已用于此目的，但这些模型明显不同于自然感染，因为 HBV 是由所有肝细胞中包含的整合 HBV 序列产生的。 方法：对 Balb/cA 裸鼠进行流体动力学注射具有超长 1.5 倍 HBV DNA 的质粒，并分析 HBV 复制。 结果：流体动力学注射的小鼠在 1 年多的时间里表现出高水平的抗原血症和病毒血症。共价闭合环状 DNA (cccDNA) 是自然感染中病毒复制的模板，在肝脏中产生，并且在 HBV 的长期产生中发挥着重要作用，因为接种 DNA 的 pol 基因的破坏导致 HBV 基因短暂表达不到 2 个月。给予IFN α基因暂时抑制了HBV DNA复制，但不能消除该模型中的HBV。结论：编码HBV DNA的质粒的体内基因转移可以在小鼠体内建立慢性病毒复制，这至少部分涉及HBV cccDNA附加体的新合成，从而重现了人类HBV感染的一部分。 (C) 2005 年欧洲肝脏研究协会。由 Elsevier B.V. 出版。保留所有权利。
Background/Aims: The lack of small animal models supporting chronic hepatitis B virus (HBV) infection impedes the assessment of anti-viral drugs in the whole animal. Although transgenic mice have been used for this purpose, these models are clearly different from natural infection, because HBV is produced from the integrated HBV sequence harbored in all hepatocytes.Methods: Balb/cA nude mice were hydrodynamically injected with a plasmid having 1.5-fold over-length of HBV DNA and analyzed for HBV replication.Results: Hydrodynamically injected mice showed substantial levels of antigenemia and viremia for more than 1 year. Covalently closed circular DNA (cccDNA), the template of viral replication in natural infection, was produced in the livers and was critically involved in the long-term HBV production, because disruption of the pol gene of the inoculated DNA resulted in transient expression of HBV genes for less than 2 months. Administration of the IFN alpha gene transiently suppressed HBV DNA replication, but was not capable of eliminating HBV in this model.Conclusions: In vivo gene transfer of a plasmid encoding HBV DNA can establish chronic viral replication in mice, which involves, at least in part, new synthesis of the HBV cccDNA episome, thus recapitulating a part of human HBV infection. (C) 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.