Cell entry of hepatitis C virus requires a set of co-receptors that include the CD81 tetraspanin and the SR-B1 scavenger receptor
Cell entry of hepatitis C virus requires a set of co-receptors that include the CD81 tetraspanin and the SR-B1 scavenger receptor
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DOI：
10.1074/jbc.m305289200
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发表时间：
2003-10-24
影响因子：
4.8
通讯作者：
Cosset, FL
中科院分区：
文献类型：
--
作者：
Bartosch, B;Vitelli, A;Cosset, FL
几种细胞表面分子已被提议作为候选受体，根据其与病毒体或可溶性 HCV E2 糖蛋白的物理关联来介导丙型肝炎病毒 (HCV) 进入细胞。然而，由于缺乏传染性 HCV 颗粒，这些候选受体支持感染的证据缺失。使用我们最近描述的显示功能性 E1E2 糖蛋白复合物的传染性 HCV 假型颗粒 (HCVpp)，我们在此表明 HCV 是一种 pH 依赖性病毒，这意味着其受体成分通过内吞作用介导病毒颗粒内化。 CD81 四跨膜蛋白在不允许的 CD81 阴性肝癌细胞中的表达足以恢复对 HCVpp 感染的易感性，证实了其作为细胞附着因子的关键作用。作为一种可能介导内体运输的细胞表面分子，我们证明了人类 B 型清道夫受体 1 型 (SR-B1) 是感染表达 CD81 的肝细胞所必需的，这是一种高密度脂蛋白内化分子，我们之前因其与 E2 糖蛋白的亲和力而提出作为新型 HCV 受体候选者。通过受体竞争测定，我们发现阻断可溶性 E2 结合的 SR-B1 抗体可以预防 HCVpp 感染。此外，我们确定 HCV E2 糖蛋白的高变区 1 是介导 SR-B1 阳性细胞进入的关键决定因素。最后，通过将 HCV 受体的表达与感染性联系起来，我们认为，除了 CD81 和 SR-B1 之外，HCV 进入还需要其他肝细胞特异性辅助因子。
Several cell surface molecules have been proposed as receptor candidates, mediating cell entry of hepatitis C virus (HCV) on the basis of their physical association with virions or with soluble HCV E2 glycoproteins. However, due to the lack of infectious HCV particles, evidence that these receptor candidates support infection was missing. Using our recently described infectious HCV pseudotype particles (HCVpp) that display functional E1E2 glycoprotein complexes, here we show that HCV is a pH-dependent virus, implying that its receptor component(s) mediate virion internalization by endocytosis. Expression of the CD81 tetraspanin in non-permissive CD81-negative hepato-carcinoma cells was sufficient to restore susceptibility to HCVpp infection, confirming its critical role as a cell attachment factor. As a cell surface molecule likely to mediate endosomal trafficking, we demonstrate that the human scavenger receptor class B type 1 (SR-B1), a high-density lipoprotein-internalization molecule that we previously proposed as a novel HCV receptor candidate due to its affinity with E2 glycoproteins, is required for infection of CD81-expressing hepatic cells. By receptor competition assays, we found that SR-B1 antibodies that blocked binding of soluble E2 could prevent HCVpp infectivity. Furthermore, we establish that the hyper-variable region 1 of the HCV E2 glycoprotein is a critical determinant mediating entry in SR-B1-positive cells. Finally, by correlating expression of HCV receptors and infectivity, we suggest that, besides CD81 and SR-B1, additional hepatocyte-specific co-factor(s) are necessary for HCV entry.