Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France.
Hepatology. 2012 Apr;55(4):998-1007. doi: 10.1002/hep.25501.
Hepatitis C virus (HCV) particles are known to be in complex with lipoproteins. As a result of this interaction, the low-density lipoprotein (LDL) receptor (LDLR) has been proposed as a potential entry factor for HCV; however, its implication in virus entry remains unclear. Here, we reinvestigated the role of the LDLR in the HCV life cycle by comparing virus entry to the mechanism of lipoprotein uptake. A small interfering RNA targeting the LDLR in Huh-7 cells reduced HCV infectivity, confirming that this receptor plays a role in the life cycle of HCV generated in cell culture. However, kinetics of internalization were much faster for lipoproteins than for infectious HCV particles. Furthermore, a decrease in HCV RNA replication was observed by blocking the LDLR with a specific antibody, and this was associated with an increase in the ratio of phosphatidylethanolamine to phosphatidylcholine in host cells. Nevertheless, a soluble form of the LDLR inhibited both HCV entry into the hepatocytes and its binding to the LDLR expressed on Chinese hamster ovary cells, suggesting a direct interaction between the HCV particle and the LDLR. Finally, we showed that modification of HCV particles by lipoprotein lipase (LPL) reduces HCV infectivity and increases HCV binding to LDLR. Importantly, LPL treatment also induced an increase in RNA internalization, suggesting that LDLR, at least in some conditions, leads to nonproductive internalization of HCV.
The LDLR is not essential for infectious HCV particle entry, whereas the physiological function of this receptor is important for optimal replication of the HCV genome.
已知丙型肝炎病毒 (HCV) 颗粒与脂蛋白复合物。由于这种相互作用，低密度脂蛋白 (LDL) 受体 (LDLR) 被提议作为 HCV 的潜在进入因素；然而，其在病毒进入中的作用仍不清楚。在这里，我们通过比较脂蛋白摄取的机制来重新研究 LDLR 在 HCV 生命周期中的作用。在 Huh-7 细胞中靶向 LDLR 的小干扰 RNA 降低了 HCV 的感染力，证实该受体在细胞培养中产生的 HCV 生命周期中发挥作用。然而，脂蛋白的内化动力学比感染性 HCV 颗粒快得多。此外，用特异性抗体阻断 LDLR 观察到 HCV RNA 复制减少，这与宿主细胞中磷脂酰乙醇胺与磷脂酰胆碱的比例增加有关。然而，LDLR 的可溶性形式抑制了 HCV 进入肝细胞及其与在中华仓鼠卵巢细胞上表达的 LDLR 的结合，表明 HCV 颗粒与 LDLR 之间存在直接相互作用。最后，我们表明脂蛋白脂肪酶 (LPL) 对 HCV 颗粒的修饰降低了 HCV 的感染力，并增加了 HCV 与 LDLR 的结合。重要的是，LPL 处理还诱导了 RNA 内化的增加，这表明 LDLR 至少在某些条件下导致 HCV 的非生产性内化。
LDLR 不是感染性 HCV 颗粒进入所必需的，而该受体的生理功能对于 HCV 基因组的最佳复制很重要。
