Reynolds Gary M, Harris Helen J, Jennings Adam, Hu Ke, Grove Joe, Lalor Patricia F, Adams David H, Balfe Peter, Hübscher Stefan G, McKeating Jane A
Liver Laboratories, Institute for Biomedical Research, University of Birmingham and University Hospital Birmingham NHS Foundation Trust, Birmingham, United Kingdom.
Hepatology. 2008 Feb;47(2):418-27. doi: 10.1002/hep.22028.
The principal site of hepatitis C virus (HCV) replication is the liver. HCV pseudoparticles infect human liver derived cell lines and this suggests that liver-specific receptors contribute to defining HCV hepatotropism. At least three host cell molecules have been reported to be important for HCV entry: the tetraspanin CD81, scavenger receptor class B member I (SR-BI), and the tight junction (TJ) protein Claudin 1 (CLDN1). Hepatocytes in liver tissue coexpress CD81, SR-BI, and CLDN1, consistent with their ability to support HCV entry. CLDN1 localized at the apical-canalicular TJ region and at basolateral-sinusoidal hepatocyte surfaces in normal tissue and colocalized with CD81 at both sites. In contrast, CLDN1 appeared to colocalize with SR-BI at the basolateral-sinusoidal surface. CLDN1 expression was increased on basolateral hepatocyte membranes in HCV-infected and other chronically inflamed liver tissue compared with normal liver. In contrast, CLDN4 hepatocellular staining was comparable in normal and diseased liver tissue.
HCV infection of Huh-7.5 hepatoma cells in vitro significantly increased CLDN1 expression levels, consistent with a direct modulation of CLDN1 by virus infection. In HCV infected livers, immunohistochemical studies revealed focal patterns of CLDN1 staining, suggesting localized areas of increased CLDN1 expression in vivo which may potentiate local viral spread within the liver.
丙型肝炎病毒（HCV）复制的主要部位是肝脏。HCV假病毒颗粒可感染源自人肝脏的细胞系，这表明肝脏特异性受体有助于确定HCV的嗜肝性。据报道，至少有三种宿主细胞分子对HCV进入至关重要：四跨膜蛋白CD81、B类清道夫受体成员I（SR-BI）和紧密连接（TJ）蛋白Claudin 1（CLDN1）。肝组织中的肝细胞共表达CD81、SR-BI和CLDN1，这与其支持HCV进入的能力一致。在正常组织中，CLDN1定位于顶端胆小管TJ区域和基底外侧窦状肝细胞表面，并在这两个部位与CD81共定位。相比之下，CLDN1似乎在基底外侧窦状表面与SR-BI共定位。与正常肝脏相比，在HCV感染的肝脏和其他慢性炎症肝脏组织中，基底外侧肝细胞膜上的CLDN1表达增加。相比之下，正常和患病肝脏组织中CLDN4的肝细胞染色相当。
体外Huh-7.5肝癌细胞的HCV感染显著增加了CLDN1表达水平，这与病毒感染对CLDN1的直接调节一致。在HCV感染的肝脏中，免疫组织化学研究显示CLDN1染色呈局灶性模式，表明体内CLDN1表达增加的局部区域可能会促进肝脏内局部病毒传播。
