High-avidity monoclonal antibodies against the human scavenger class B type I receptor efficiently block hepatitis C virus infection in the presence of high-density lipoprotein
High-avidity monoclonal antibodies against the human scavenger class B type I receptor efficiently block hepatitis C virus infection in the presence of high-density lipoprotein
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DOI：
10.1128/jvi.00193-07
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发表时间：
2007-08-01
影响因子：
5.4
通讯作者：
Nicosia, Alfredo
中科院分区：
文献类型：
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作者：
Catanese, Maria Teresa;Graziani, Rita;Nicosia, Alfredo
人清道夫B类1型受体（SR-B1/Cia 1）被鉴定为丙型肝炎病毒（HCV）的推定受体，因为它结合可溶性重组HCV包膜糖蛋白E2（sE 2）。高密度脂蛋白（HDL），一种天然的SR-B1配体，被证明可以增加携带HCV包膜糖蛋白的逆转录病毒假颗粒和细胞培养衍生的HCV（HCVRNA）的体外感染性，这表明SR-B1以HDL依赖的方式促进病毒进入。为了确定SR-B1是否直接参与HCV感染或通过脂蛋白摄取促进HCV进入，我们产生了一组针对天然人SR-B1的单克隆抗体（MAbs）。其中两个，3D 5和C167，结合到构象依赖的SR-B1决定簇和抑制sE 2与SR-B1的相互作用。这些抗体以剂量依赖性方式有效地阻断了Huh-7.5肝癌细胞的HCVRNA感染。为了研究HDL在SR-B1介导的HCV 3感染中的作用，我们在无血清培养基中建立HCV 3产生和感染的条件。在没有血清脂蛋白的情况下，HCCP有效地感染Huh-7.5细胞，并且添加HDL导致感染性增加两倍。然而，HDL诱导的感染增强对单克隆抗体C167的中和效力没有影响，尽管其能够抑制HDL与细胞的结合和SR-B1介导的脂质转移。值得注意的是，MAb C167还有效地阻断了从HCVcc感染的黑猩猩中回收的HCV毒株引起的Huh-7.5感染。这些结果表明，SR-B1是必不可少的体外和体内产生的HCV感染，并建议抗SR-B1抗体作为治疗剂的可能用途。
The human scavenger class B type 1 receptor (SR-B1/Cia1) was identified as a putative receptor for hepatitis C virus (HCV) because it binds to soluble recombinant HCV envelope glycoprotein E2 (sE2). High-density lipoprotein (HDL), a natural SR-B1 ligand, was shown to increase the in vitro infectivity of retroviral pseudoparticles bearing HCV envelope glycoproteins and of cell culture-derived HCV (HCVcc), suggesting that SR-B1 promotes viral entry in an HDL-dependent manner. To determine whether SR-B1 participates directly in HCV infection or facilitates HCV entry through lipoprotein uptake, we generated a panel of monoclonal antibodies (MAbs) against native human SR-B1. Two of them, 3D5 and C167, bound to conformation-dependent SR-B1 determinants and inhibited the interaction of sE2 with SR-B1. These antibodies efficiently blocked HCVcc infection of Huh-7.5 hepatoma cells in a dose-dependent manner. To examine the role of HDL in SR-B1-mediated HCVcc infection, we set up conditions for HCVcc production and infection in serum-free medium. HCVcc efficiently infected Huh-7.5 cells in the absence of serum lipoproteins, and addition of HDL led to a twofold increase in infectivity. However, the HDL-induced enhancement of infection had no impact on the neutralization potency of MAb C167, despite its ability to inhibit both HDL binding to cells and SR-B1-mediated lipid transfer. Of note, MAb C167 also potently blocked Huh-7.5 infection by an HCV strain recovered from HCVcc-infected chimpanzees. These results demonstrate that SR-B1 is essential for infection with HCV produced in vitro and in vivo and suggest the possible use of anti-SR-B1 antibodies as therapeutic agents.