HIGH-LEVEL HEPATITIS-B VIRUS-REPLICATION IN TRANSGENIC MICE
HIGH-LEVEL HEPATITIS-B VIRUS-REPLICATION IN TRANSGENIC MICE
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DOI：
10.1128/jvi.69.10.6158-6169.1995
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发表时间：
1995-10-01
影响因子：
5.4
通讯作者：
CHISARI, FV
中科院分区：
文献类型：
--
作者：
GUIDOTTI, LG;MATZKE, B;CHISARI, FV
已经产生了B型肝炎病毒（HBV）转基因小鼠，其肝细胞复制病毒的水平与慢性肝炎患者感染的肝脏相当，而没有任何细胞病理学证据。在三个独立谱系的肝和肾组织中获得了高水平的病毒基因表达。这些动物是用末端冗余病毒DNA构建体（HBV 1.3）生产的，该构建体起始于HBV增强子I的上游，完全围绕环状病毒基因组延伸，并终止于HBV中独特的聚腺苷酸化位点的下游。在这些动物中，病毒mRNA在小叶中心肝细胞中比在肝小叶的其他地方更丰富。高水平的病毒DNA复制发生在病毒核衣壳颗粒内，这些颗粒优先形成于这些小叶中心肝细胞的细胞质中，这表明必须达到表达阈值才能发生核衣壳组装和病毒复制。尽管在小叶中心的细胞质核衣壳中的病毒复制机制的分布有限，但在整个肝小叶的绝大多数肝细胞核中都可检测到核衣壳颗粒。然而，核内核衣壳颗粒是空的，这表明病毒核衣壳颗粒组装独立地发生在肝细胞的细胞核和细胞质中，并意味着细胞质核衣壳颗粒在病毒生命周期期间不将病毒基因组转运穿过核膜进入细胞核，该模型为研究病毒和宿主因素对HBV发病机制和复制的影响以及评估药理学和生理学药物的抗病毒潜力创造了机会。过程，包括免疫反应。
Hepatitis B virus (HBV) transgenic mice whose hepatocytes replicate the virus at levels comparable to that in the infected livers of patients,vith chronic hepatitis have been produced, without any evidence of cytopathology. High-level viral gene expression was obtained in the liver and kidney tissues in three independent lineages. These animals were produced with a terminally redundant viral DNA construct (HBV 1.3) that starts just upstream of HBV enhancer I, extends completely around the circular viral genome, and ends just downstream of the unique polyadenylation site in HBV. In these animals, the viral mRNA is more abundant in centrilobular hepatocytes than elsewhere in the hepatic lobule. High-level viral DNA replication occurs inside viral nucleocapsid particles that preferentially form in the cytoplasm of these centrilobular hepatocytes, suggesting that an expression threshold must be reached for nucleocapsid assembly and viral replication to occur. Despite the restricted distribution of the viral replication machinery in centrilobular cytoplasmic nucleocapsids, nucleocapsid particles are detectable in the vast majority of hepatocyte nuclei throughout the hepatic lobule. The intranuclear nucleocapsid particles are empty, however, suggesting that viral nucleocapsid particle assembly occurs independently in the nucleus and the cytoplasm of the hepatocyte and implying that cytoplasmic nucleocapsid particles do not transport the viral genome across the nuclear membrane into the nucleus during the viral life cycle, This model creates the opportunity to examine the influence of viral and host factors on HBV pathogenesis and replication and to assess the antiviral potential of pharmacological agents and physiological processes, including the immune response.