High resolution sequencing of hepatitis C virus reveals limited intra-hepatic compartmentalization in end-stage liver disease.
High resolution sequencing of hepatitis C virus reveals limited intra-hepatic compartmentalization in end-stage liver disease.
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DOI：
10.1016/j.jhep.2016.07.048
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发表时间：
2017-01
影响因子：
25.7
通讯作者：
McKeating JA
中科院分区：
文献类型：
--
作者：
Hedegaard DL;Tully DC;Rowe IA;Reynolds GM;Bean DJ;Hu K;Davis C;Wilhelm A;Ogilvie CB;Power KA;Tarr AW;Kelly D;Allen TM;Balfe P;McKeating JA
丙型肝炎病毒（HCV）的高复制和突变率导致体内病毒序列的异质性群体。HCV在肝脏和受感染肝细胞中的复制作为被未感染细胞包围的病灶发生，这可能促进病毒变体的区室化。鉴于最近的报道显示干扰素刺激基因（ISG）在慢性丙型肝炎中的表达，我们假设局部干扰素反应可能限制HCV的复制和演变。为了研究肝脏结构对病毒复制的空间影响，我们检测了21例接受肝移植的患者的8个Couinaud肝段的HCV RNA和ISG mRNA。HCV RNA和ISG mRNA水平在来自个体肝脏的所有位点之间相当，但在患者之间显示高达500倍的差异。重要的是，在肝脏或血浆中的所有位点，ISG和HCV RNA表达之间没有关联。从两名受试者的8个肝脏部位分离的HCV RNA的深度测序显示，肝脏中病毒准种的分布相似，序列多样性一致。在2个肝脏位点从6个选定的患者中扩增的HCV E1E2包膜克隆的单基因组支持这些数据，并且没有显示HCV区室化的证据。我们发现在所有采样的患者中，肝脏和血浆病毒准种之间没有差异。我们的结论是，在终末期肝病HCV RNA水平和HCV包膜序列的基因库之间的肝脏和血浆中的遥远的网站是无法区分的，反对病毒区室化。HCV是一种RNA病毒，其作为密切相关基因组的准种存在，所述基因组在宿主先天性和适应性免疫应答以及抗病毒药物治疗的持续选择下。丙型肝炎病毒复制的主要部位是肝脏，但我们对肝脏内病毒变体的空间分布的了解有限。HCV的高分辨率测序和对肝脏多个部位先天免疫反应的监测发现了一种统一的多样性模式，并反对病毒区室化。
The high replication and mutation rate of hepatitis C virus (HCV) results in a heterogeneous population of viral sequences in vivo. HCV replicates in the liver and infected hepatocytes occur as foci surrounded by uninfected cells that may promote compartmentalization of viral variants. Given recent reports showing interferon stimulated gene (ISG) expression in chronic hepatitis C, we hypothesized that local interferon responses may limit HCV replication and evolution. To investigate the spatial influence of liver architecture on viral replication we measured HCV RNA and ISG mRNA from each of the 8 Couinaud segments of the liver from 21 patients undergoing liver transplant. HCV RNA and ISG mRNA levels were comparable across all sites from an individual liver but showed up to 500-fold difference between patients. Importantly, there was no association between ISG and HCV RNA expression across all sites in the liver or plasma. Deep sequencing of HCV RNA isolated from the 8 hepatic sites from two subjects showed a similar distribution of viral quasispecies across the liver and uniform sequence diversity. Single genome amplification of HCV E1E2-envelope clones from 6 selected patients at 2 hepatic sites supported these data and showed no evidence for HCV compartmentalization. We found no differences between the hepatic and plasma viral quasispecies in all patients sampled. We conclude that in end-stage liver disease HCV RNA levels and the genetic pool of HCV envelope sequences are indistinguishable between distant sites in the liver and plasma, arguing against viral compartmentalization. HCV is an RNA virus that exists as a quasispecies of closely related genomes that are under continuous selection by host innate and adaptive immune responses and antiviral drug therapy. The primary site of HCV replication is the liver and yet our understanding of the spatial distribution of viral variants within the liver is limited. High resolution sequencing of HCV and monitoring of innate immune responses at multiple sites across the liver identified a uniform pattern of diversity and argues against viral compartmentalization.
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影响因子：
4.3
作者：
Graw, Frederik;Balagopal, Ashwin;Perelson, Alan S.
通讯作者：
Perelson, Alan S.
影响因子：
3.7
作者：
Gregori J;Esteban JI;Cubero M;Garcia-Cehic D;Perales C;Casillas R;Alvarez-Tejado M;Rodríguez-Frías F;Guardia J;Domingo E;Quer J
通讯作者：
Quer J
影响因子：
6.6
作者：
Guillot, Gilles;Rousset, Francois
通讯作者：
Rousset, Francois
影响因子：
64.5
作者：
CHEYNIER, R;HENRICHWARK, S;WAINHOBSON, S
通讯作者：
WAINHOBSON, S
影响因子：
5.4
作者：
Cabot, B;Martell, M;Gómez, J
通讯作者：
Gómez, J