The Amount of Hepatocyte Turnover That Occurred during Resolution of Transient Hepadnavirus Infections Was Lower When Virus Replication Was Inhibited with Entecavir
The Amount of Hepatocyte Turnover That Occurred during Resolution of Transient Hepadnavirus Infections Was Lower When Virus Replication Was Inhibited with Entecavir
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DOI：
10.1128/jvi.01587-08
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发表时间：
2009-02-15
影响因子：
5.4
通讯作者：
Jilbert, Allison R.
中科院分区：
文献类型：
--
作者：
Mason, William S.;Xu, Chunxiao;Jilbert, Allison R.
一过性肝炎病毒感染可涉及病毒向整个肝细胞群的传播。在这种情况下，康复后出现的肝细胞来自感染的肝细胞。在病毒清除过程中，抗病毒细胞因子被认为可以阻止病毒复制和形成新的共价闭合环状DNA(CccDNA)，这是病毒的转录模板。目前尚不清楚现有的cccDNA是否是以非细胞溶解的方式消除，或者是否需要肝细胞的死亡和增殖来补偿一些被感染的肝细胞的死亡，以从存活的感染肝细胞中移除cccDNA。要了解肝细胞死亡与cccDNA清除的关系，既要知道肝细胞的周转量，又要知道在感染的肝细胞免疫破坏期间，cccDNA的合成是否被有效地阻断。我们通过询问病毒DNA合成的核苷类似物恩替卡韦(ETV)治疗土拨鼠是否在清除短暂性土拨鼠肝炎病毒(WHV)感染期间降低了肝细胞周转率来解决这些问题。为了估计肝细胞的周转，对WHV感染的对照或ETV处理的土拨鼠肝脏中整合WHV并呈现恢复的病毒-细胞DNA连接进行了复杂性分析。我们估计，平均而言，在ETV处理的土拨鼠的免疫清除过程中，肝细胞周转率降低了2.2到4.8倍。对复杂性数据的计算机模拟表明，在一过性感染的恢复过程中，除了肝细胞死亡之外，机制还负责消除cccDNA。
Transient hepadnavirus infections can involve spread of virus to the entire hepatocyte population. In this situation hepatocytes present following recovery are derived from infected hepatocytes. During virus clearance antiviral cytokines are thought to block virus replication and formation of new covalently closed circular DNA (cccDNA), the viral transcriptional template. It remains unclear if existing cccDNA is eliminated noncytolytically or if hepatocyte death and proliferation, to compensate for killing of some of the infected hepatocytes, are needed to remove cccDNA from surviving infected hepatocytes. Interpreting the relationship between hepatocyte death and cccDNA elimination requires knowing both the amount of hepatocyte turnover and whether cccDNA synthesis is effectively blocked during the period of immune destruction of infected hepatocytes. We have addressed these questions by asking if treatment of woodchucks with the nucleoside analog inhibitor of viral DNA synthesis entecavir (ETV) reduced hepatocyte turnover during clearance of transient woodchuck hepatitis virus (WHV) infections. To estimate hepatocyte turnover, complexity analysis was carried out on virus-cell DNA junctions created by integration of WHV and present following recovery in the livers of WHV-infected control or ETV-treated woodchucks. We estimated that, on average, 2.2 to 4.8 times less hepatocyte turnover occurred during immune clearance in the ETV-treated woodchucks. Computer modeling of the complexity data suggests that mechanisms in addition to hepatocyte death were responsible for elimination of cccDNA during recovery from transient infections.