Gardner Jason P, Durso Robert J, Arrigale Robert R, Donovan Gerald P, Maddon Paul J, Dragic Tatjana, Olson William C
Progenics Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4498-503. doi: 10.1073/pnas.0831128100. Epub 2003 Apr 3.
Hepatitis C virus (HCV) infects nearly 3% of the population of the world and is a major cause of liver disease. However, the mechanism whereby the virus targets the liver for infection remains unknown, because none of the putative cellular receptors for HCV are both expressed specifically in the liver and capable of binding HCV envelope glycoproteins. Liver/lymph node-specific intercellular adhesion molecule-3-grabbing integrin (L-SIGN) is a calcium-dependent lectin expressed on endothelial cells of liver and lymph nodes. Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), a homologous molecule expressed on dendritic cells, binds HIV and promotes infection. By using a virus-binding assay, we demonstrate that L-SIGN and DC-SIGN specifically bind naturally occurring HCV present in the sera of infected individuals. Further studies demonstrate that binding is mediated by the HCV envelope glycoprotein E2 and is blocked by specific inhibitors, including mannan, calcium chelators, and Abs to the lectin domain of the SIGN molecules. Thus, L-SIGN represents a liver-specific receptor for HCV, and L-SIGN and DC-SIGN may play important roles in HCV infection and immunity.
丙型肝炎病毒(HCV)感染了近3%的世界人口,是肝脏疾病的主要病因。然而,该病毒靶向肝脏进行感染的机制仍不清楚,因为HCV的假定细胞受体中没有一种在肝脏中特异性表达且能够结合HCV包膜糖蛋白。肝脏/淋巴结特异性细胞间黏附分子3结合整合素(L-SIGN)是一种在肝脏和淋巴结内皮细胞上表达的钙依赖性凝集素。树突状细胞特异性细胞间黏附分子3结合非整合素(DC-SIGN),一种在树突状细胞上表达的同源分子,可结合HIV并促进感染。通过病毒结合试验,我们证明L-SIGN和DC-SIGN特异性结合感染个体血清中天然存在的HCV。进一步研究表明,这种结合由HCV包膜糖蛋白E2介导,并被包括甘露聚糖、钙螯合剂和针对SIGN分子凝集素结构域的抗体在内的特异性抑制剂所阻断。因此,L-SIGN代表HCV的肝脏特异性受体,L-SIGN和DC-SIGN可能在HCV感染和免疫中发挥重要作用。