Inferring Viral Dynamics in Chronically HCV Infected Patients from the Spatial Distribution of Infected Hepatocytes
Inferring Viral Dynamics in Chronically HCV Infected Patients from the Spatial Distribution of Infected Hepatocytes
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DOI：
10.1371/journal.pcbi.1003934
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发表时间：
2014-11-01
影响因子：
4.3
通讯作者：
Perelson, Alan S.
中科院分区：
文献类型：
--
作者：
Graw, Frederik;Balagopal, Ashwin;Perelson, Alan S.
丙型肝炎病毒(丙型肝炎病毒)的慢性肝脏感染是一个主要的公共卫生问题。尽管部分治疗方案取得了成功，但对肝内丙型肝炎病毒感染动态的几个方面仍然知之甚少，包括病毒传播的首选模式，以及感染肝细胞的比例。对这些问题的回答对治疗干预措施的发展具有重要意义。在这项研究中，我们提出了通过单细胞激光捕获显微切割从慢性丙型肝炎患者的肝活检标本中分析感染肝细胞的空间分布的方法。通过表征感染细胞团的内部结构，我们能够评估有关肝内感染动力学的假说。我们发现，活检样本上的单个簇的大小从4-50个感染细胞不等。此外，一个簇中的丙型肝炎病毒RNA含量从推测建立簇的细胞下降到最大簇扩展的细胞。这些观察结果支持这样一种观点，即肝脏中的丙型肝炎病毒感染是随机传播的(例如，从血液中)，然后在局部传播。假设细胞内的丙型肝炎病毒RNA的量是细胞感染时间的替代，我们基于细胞内丙型肝炎病毒RNA复制和积累的模型估计，集群中的细胞平均感染不到一周。此外，我们没有发现集群大小和估计的集群扩展时间之间的关系。我们的方法代表了一种新的方法来从静态空间数据中推断固体组织中的感染动力学。
Chronic liver infection by hepatitis C virus (HCV) is a major public health concern. Despite partly successful treatment options, several aspects of intrahepatic HCV infection dynamics are still poorly understood, including the preferred mode of viral propagation, as well as the proportion of infected hepatocytes. Answers to these questions have important implications for the development of therapeutic interventions. In this study, we present methods to analyze the spatial distribution of infected hepatocytes obtained by single cell laser capture microdissection from liver biopsy samples of patients chronically infected with HCV. By characterizing the internal structure of clusters of infected cells, we are able to evaluate hypotheses about intrahepatic infection dynamics. We found that individual clusters on biopsy samples range in size from 4-50 infected cells. In addition, the HCV RNA content in a cluster declines from the cell that presumably founded the cluster to cells at the maximal cluster extension. These observations support the idea that HCV infection in the liver is seeded randomly (e. g. from the blood) and then spreads locally. Assuming that the amount of intracellular HCV RNA is a proxy for how long a cell has been infected, we estimate based on models of intracellular HCV RNA replication and accumulation that cells in clusters have been infected on average for less than a week. Further, we do not find a relationship between the cluster size and the estimated cluster expansion time. Our method represents a novel approach to make inferences about infection dynamics in solid tissues from static spatial data.