Scavenger receptor BI and BII expression levels modulate hepatitis C virus infectivity
Scavenger receptor BI and BII expression levels modulate hepatitis C virus infectivity
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DOI：
10.1128/jvi.02356-06
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发表时间：
2007-04-01
影响因子：
5.4
通讯作者：
McKeating, Jane A.
中科院分区：
文献类型：
--
作者：
Grove, Joe;Huby, Thierry;McKeating, Jane A.
丙型肝炎病毒（HCV）通过pH和网格蛋白依赖性内吞途径进入细胞。清道夫受体BI（SR-BI）和CD 81是HCV内化进入靶细胞的重要进入因子。SR-BI基因产生至少两种mRNA剪接变体，SR-BI和SR-BII，它们的C末端不同。SR-BI内化仍然知之甚少，但据报道SR-BII通过网格蛋白依赖性途径内吞，使其成为HCV内化的有吸引力的靶点。我们证明HCV可溶性E2可以与人SR-BI和SR-BII相互作用。SR-BI和SR-BII在Huh-7.5肝癌细胞系中表达的增加增强了HCV株J6/JFH和JFH的感染性，表明这些受体的内源性水平限制了感染。SR-BI而非SR-BH的表达升高增加了J6/JFH感染的速率，这可能反映了剪接变体的细胞内运输改变。在人血浆中，已报道HCV颗粒与脂蛋白复合，表明病毒与SR-BI和其他脂蛋白受体的间接相互作用。来自移植有人肝细胞的J6/JFH感染的uPA-SCID小鼠的血浆证明了对SR-BI/II过表达的Huh-7.5细胞的感染性增加。血浆来源的J6/JFH感染性被抗E2单克隆抗体抑制，表明血浆病毒与SR-BI的相互作用是糖蛋白依赖性的。最后，抗SR-BI抗体抑制细胞培养物和血浆来源的J6/JFH的感染性，表明SR-BI/II在HCV感染中的关键作用。
Hepatitis C virus (HCV) enters cells via a pH- and clathrin-dependent endocytic pathway. Scavenger receptor BI (SR-BI) and CD81 are important entry factors for HCV internalization into target cells. The SR-BI gene gives rise to at least two mRNA splice variants, SR-BI and SR-BII, which differ in their C termini. SR-BI internalization remains poorly understood, but SR-BII is reported to endocytose via a clathrin-dependent pathway, making it an attractive target for HCV internalization. We demonstrate that HCV soluble E2 can interact with human SR-BI and SR-BII. Increased expression of SR-BI and SR-BII in the Huh-7.5 hepatoma cell line enhanced HCV strain J6/JFH and JFH infectivity, suggesting that endogenous levels of these receptors limit infection. Elevated expression of SR-BI, but not SR-BH, increased the rate of J6/JFH infection, which may reflect altered intracellular trafficking of the splice variants. In human plasma, HCV particles have been reported to be complexed with lipoproteins, suggesting an indirect interaction of the virus with SR-BI and other lipoprotein receptors. Plasma from J6/JFH-infected uPA-SCID mice transplanted with human hepatocytes demonstrates an increased infectivity for SR-BI/II-overexpressing Huh-7.5 cells. Plasma-derived J6/JFH infectivity was inhibited by an anti-E2 monoclonal antibody, suggesting that plasma virus interaction with SR-BI was glycoprotein dependent. Finally, anti-SR-BI antibodies inhibited the infectivity of cell culture- and plasma-derived J6/JFH, suggesting a critical role for SR-BI/II in HCV infection.