Three Different Functional Microdomains in the Hepatitis C Virus Hypervariable Region 1 (HVR1) Mediate Entry and Immune Evasion
Three Different Functional Microdomains in the Hepatitis C Virus Hypervariable Region 1 (HVR1) Mediate Entry and Immune Evasion
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丙型肝炎病毒高变区 1 (HVR1) 中的三个不同功能微结构域介导进入和免疫逃避。
DOI：
10.1074/jbc.m112.382341
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发表时间：
2012-10-12
影响因子：
4.8
通讯作者：
Qi, Zhongtian
中科院分区：
文献类型：
--
作者：
Guan, Mo;Wang, Wenbo;Qi, Zhongtian
高度遗传异质性是丙型肝炎病毒（HCV）的重要特征，有助于其建立持续感染的能力。包括E2包膜糖蛋白的前27个氨基酸残基的高变区1（HVR 1）是HCV多蛋白内最可变的区域。HVR 1在HCV细胞进入和免疫逃避中起主要作用，但具体氨基酸残基的各自贡献仍不清楚。我们使用H77分离株对HCV假颗粒和细胞培养物衍生的HCV进行的诱变分析表明，位置14、15和25-27处的5个残基介导E2蛋白与清道夫受体B类、I型受体的结合，并且本文中的任何残基对于HCV细胞进入都是必不可少的。跨越位置16-24的区域含有唯一的中和表位，并且对于HCV进入是不稳定的，但它参与乙酰肝素结合。更重要的是，该区域是增强HCV通过高密度脂蛋白进入所必需的，并干扰E2中和抗体对病毒的中和。1-13位的残基也是HCV进入所必需的，但它们可以通过调节包膜蛋白与I型B类清道夫受体的结合来影响HCV感染性。在该位点发生的突变可能赋予对HVR 1抗体的抗性。这些发现进一步加深了我们对HCV进入细胞的机制以及HVR 1变异在HCV免疫逃逸中的意义的理解。它们对HCV进入抑制剂和预防性疫苗的开发具有重要意义。
High genetic heterogeneity is an important characteristic of hepatitis C virus (HCV) that contributes to its ability to establish persistent infection. The hypervariable region 1 (HVR1) that includes the first 27 amino acid residues of the E2 envelope glycoprotein is the most variable region within the HCV polyprotein. HVR1 plays a major role in both HCV cell entry and immune evasion, but the respective contribution of specific amino acid residues is still unclear. Our mutagenesis analyses of HCV pseudoparticles and cell culture-derived HCV using the H77 isolate indicate that five residues at positions 14, 15, and 25-27 mediate binding of the E2 protein to the scavenger receptor class B, type I receptor, and any residue herein is indispensable for HCV cell entry. The region spanning positions 16-24 contains the sole neutralizing epitope and is dispensable for HCV entry, but it is involved in heparan binding. More importantly, this region is necessary for the enhancement of HCV entry by high density lipoprotein and interferes with virus neutralization by E2-neutralizing antibodies. Residues at positions 1-13 are also dispensable for HCV entry, but they can affect HCV infectivity by modulating binding of the envelope protein to scavenger receptor class B, type I. Mutations occurring at this site may confer resistance to HVR1 antibodies. These findings further our understanding about the mechanisms of HCV cell entry and the significance of HVR1 variation in HCV immune evasion. They have major implications for the development of HCV entry inhibitors and prophylactic vaccines.