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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Expansion and contraction of the hepatitis B virus transcriptional template in infected chimpanzees
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Expansion and contraction of the hepatitis B virus transcriptional template in infected chimpanzees

机译：乙型肝炎病毒转录模板在受感染的黑猩猩中的扩增和收缩

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We have previously shown that hepatitis B virus (HBV) replication is controlled by noncytolytic mechanisms that depend primarily on the effector functions of the CD8~+ T cell response, especially the production of IFN-γ in the liver. The mechanisms that control the nuclear pool of viral covalently closed circular DNA (cccDNA) transcriptional template of HBV, which must be eliminated to eradicate infection, have been difficult to resolve. To examine those mechanisms, we quantitated intrahepatic HBV cccDNA levels in acutely infected chimpanzees whose virological, immunological, and pathological features were previously described. Our results demonstrate that the elimination kinetics of the cccDNA are more rapid than the elimination of HBV antigen-positive hepatocytes during the early phase of viral clearance, and they coincide with the influx of small numbers of IFN-γ producing CD8~+ T cells into the liver. In contrast, terminal clearance of the cccDNA is associated with the peak of liver disease and hepatocellular turnover and with a surge of IFN-γ producing CD8~+ T cells in the liver. Collectively, these results suggest that cccDNA clearance is a two-step process mediated by the cellular immune response. The first step reduces the pool of cccDNA molecules noncytolytically, probably by eliminating their relaxed circular DNA precursors and perhaps by destabilizing them. The second step enhances this process by destroying infected hepatocytes and triggering their turnover. Surprisingly, despite this multipronged response, traces of cccDNA persist indefinitely in the liver, likely providing a continuous antigenic stimulus that confers lifelong immunity.
机译：先前我们已经表明，乙型肝炎病毒（HBV）的复制受非细胞溶解机制控制，该机制主要取决于CD8〜+ T细胞反应的效应子功能，尤其是肝脏中IFN-γ的产生。控制HBV病毒共价闭合环状DNA（cccDNA）转录模板的核库的机制很难消除，必须消除这些机制才能消除感染。为了检查这些机制，我们对急性感染的黑猩猩的肝内HBV cccDNA水平进行了定量，其先前已描述了病毒学，免疫学和病理学特征。我们的结果表明，在病毒清除的早期阶段，cccDNA的清除动力学要比清除HBV抗原阳性的肝细胞更快，并且它们与少量产生IFN-γ的CD8〜+ T细胞大量流入相吻合。肝脏。相反，cccDNA的末端清除与肝脏疾病和肝细胞更新的高峰以及肝脏中产生IFN-γ的CD8〜+ T细胞激增有关。总的来说，这些结果表明cccDNA清除是由细胞免疫应答介导的两步过程。第一步可能是通过消除其松弛的环状DNA前体并可能使其不稳定来非溶细胞地减少cccDNA分子库。第二步通过破坏感染的肝细胞并触发其更新来增强此过程。出乎意料的是，尽管有这种多方面的反应，但cccDNA的踪迹在肝脏中无限期存在，可能会提供持续的抗原刺激，从而赋予终生免疫力。

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