C-type lectins L-SIGN and DC-SIGN capture and transmit infectious hepatitis C virus pseudotype particles
C-type lectins L-SIGN and DC-SIGN capture and transmit infectious hepatitis C virus pseudotype particles
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DOI：
10.1074/jbc.m402296200
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发表时间：
2004-07-30
影响因子：
4.8
通讯作者：
Altmeyer, R
中科院分区：
文献类型：
--
作者：
Lozach, PY;Amara, A;Altmeyer, R
丙型肝炎病毒（HCV）肝嗜性的分子机制尚未确定。我们先前已经表明，肝脏表达的C型凝集素L-SIGN和DC-SIGN以高亲和力结合HCV E2糖蛋白（Lozach，P.Y.，Lortat-Jacob，H.，de Lacroix de Lavalette，A.，斯塔波利岛，Festival，S.，阿马拉，A.，Houles，C.，Fieschi，F.，Schwartz，O.，Virelizier，J. L.，Arenzana-Seisdedos，F.，和Altmeyer，R.（2003）J.Biol.Chem.278，20358-20366）。为了分析这种相互作用的功能相关性，我们产生了在病毒体表面呈递HCV糖蛋白E1和E2的假型慢病毒颗粒（HCV-pp）。高甘露糖N-聚糖存在于成熟感染性HCV-pp的E1蛋白上，并且在较小程度上存在于E2蛋白上。这种颗粒结合L-SIGN和DC-SIGN，但它们不能利用这些受体进入细胞。然而，当允许的Huh-7细胞与结合至L-SIGN或DC-SIGN阳性细胞系的HCV-pp共培养时，感染性病毒被有效地传播。通过L-SIGN或DC-SIGN的HCV-pp传播被特征性抑制剂如钙螯合剂EGTA和针对两种凝集素的凝集素碳水化合物识别结构域的单克隆抗体抑制。为了支持这种现象的生物学相关性，表达内源性DC-SIGN的树突状细胞以DC-SIGN依赖性方式高效地传播HCV-pp。我们的研究结果支持这样的假设，即C型凝集素，如肝窦内皮细胞表达的L-SIGN可以作为一个捕获受体的HCV在肝脏和传输感染性病毒粒子到邻近的肝细胞。
The molecular mechanisms involved in the hepatic tropism of hepatitis C virus (HCV) have not been identified. We have shown previously that liver-expressed C-type lectins L-SIGN and DC-SIGN bind the HCV E2 glycoprotein with high affinity (Lozach, P. Y., Lortat-Jacob, H., de Lacroix de Lavalette, A., Staropoli, I., Foung, S., Amara, A., Houles, C., Fieschi, F., Schwartz, O., Virelizier, J. L., Arenzana-Seisdedos, F., and Altmeyer, R. ( 2003) J. Biol. Chem. 278, 20358-20366). To analyze the functional relevance of this interaction, we generated pseudotyped lentivirus particles presenting HCV glycoproteins E1 and E2 at the virion surface (HCV-pp). High mannose N-glycans are present on E1 and, to a lesser extent, on E2 proteins of mature infectious HCV-pp. Such particles bind to both L-SIGN and DC-SIGN, but they cannot use these receptors for entry into cells. However, infectious virus is transmitted efficiently when permissive Huh-7 cells are cocultured with HCV-pp bound to L-SIGN or to DC-SIGN-positive cell lines. HCV-pp transmission via L-SIGN or DC-SIGN is inhibited by characteristic inhibitors such as the calcium chelator EGTA and monoclonal antibodies directed against lectin carbohydrate recognition domains of both lectins. In support of the biological relevance of this phenomenon, dendritic cells expressing endogenous DC-SIGN transmitted HCV-pp with high efficiency in a DC-SIGN-dependent manner. Our results support the hypothesis that C-type lectins such as the liver sinusoidal endothelial cell-expressed L-SIGN could act as a capture receptor for HCV in the liver and transmit infectious virions to neighboring hepatocytes.