Identification of a Residue in Hepatitis C Virus E2 Glycoprotein That Determines Scavenger Receptor BI and CD81 Receptor Dependency and Sensitivity to Neutralizing Antibodies
Identification of a Residue in Hepatitis C Virus E2 Glycoprotein That Determines Scavenger Receptor BI and CD81 Receptor Dependency and Sensitivity to Neutralizing Antibodies
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DOI：
10.1128/jvi.01569-08
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发表时间：
2008-12-15
影响因子：
5.4
通讯作者：
McKeating, Jane A.
中科院分区：
文献类型：
--
作者：
Grove, Joe;Nielsen, Soren;McKeating, Jane A.
丙型肝炎病毒（HCV）感染依赖于至少三种辅助受体：CD 81，清道夫受体BI（SR-BI）和claudin-1。这些分子如何协调HCV进入的机制尚不清楚。在这项研究中，我们证明了细胞培养适应的JFH-1突变体，在位置451（G451 R）的E2的氨基酸变化，具有降低对SR-BI的依赖性。这种改变的受体依赖性伴随着对可溶性CD 81中和的敏感性增加和重组E2与细胞表面表达的可溶性CD 81的结合增强。通过密度梯度离心分离HCV，可以分析颗粒-脂蛋白的相关性。细胞培养适应性突变改变了颗粒密度和感染性之间的关系，感染性峰值出现在比亲本病毒更高的密度。未观察到颗粒密度与SR-BI或CD 81辅助受体依赖性之间的关联。JFH-1 G451 R对gp特异性抗体的中和高度敏感，表明在病毒体表面的表位暴露增加。最后，在JFH-1颗粒密度和对中和抗体（NAb）的敏感性之间观察到关联，表明脂蛋白缔合降低颗粒对NAb的敏感性。总之，E2在位置451处的突变改变了颗粒密度和感染性之间的关系，破坏了辅助受体依赖性，并增加了病毒粒子对受体模拟物和NAb的敏感性。我们的数据表明，HCV颗粒，脂蛋白成分和病毒受体之间的平衡相互作用，允许逃避宿主免疫反应。
Hepatitis C virus (HCV) infection is dependent on at least three coreceptors: CD81, scavenger receptor BI (SR-BI), and claudin-1. The mechanism of how these molecules coordinate HCV entry is unknown. In this study we demonstrate that a cell culture-adapted JFH-1 mutant, with an amino acid change in E2 at position 451 (G451R), has a reduced dependency on SR-BI. This altered receptor dependency is accompanied by an increased sensitivity to neutralization by soluble CD81 and enhanced binding of recombinant E2 to cell surface-expressed and soluble CD81. Fractionation of HCV by density gradient centrifugation allows the analysis of particle-lipoprotein associations. The cell culture-adapted mutation alters the relationship between particle density and infectivity, with the peak infectivity occurring at higher density than the parental virus. No association was observed between particle density and SR-BI or CD81 coreceptor dependence. JFH-1 G451R is highly sensitive to neutralization by gp-specific antibodies, suggesting increased epitope exposure at the virion surface. Finally, an association was observed between JFH-1 particle density and sensitivity to neutralizing antibodies (NAbs), suggesting that lipoprotein association reduces the sensitivity of particles to NAbs. In summary, mutation of E2 at position 451 alters the relationship between particle density and infectivity, disrupts coreceptor dependence, and increases virion sensitivity to receptor mimics and NAbs. Our data suggest that a balanced interplay between HCV particles, lipoprotein components, and viral receptors allows the evasion of host immune responses.