高度基因异质性是HCV的一个重要特性，与其建立持续感染的能力有关。高突变区1 （HVR1）包括E2包膜糖蛋白的前27个氨基酸，是HCV多蛋白中最多变的区域。HVR1对于HCV的进入和免疫逃避具有重要作用，但是与之相关的具体氨基酸尚不清楚。我们利用H77病毒株的假病毒颗粒和细胞培养HCV进行的变异分析提示HCR1的5个氨基酸14、15和25-27介导E2蛋白与SR-BI受体的结合，与HCV进入有关。跨区域的16-24氨基酸包含主要中和位点，与HCV进入无关，但是与类肝素吸附有关。更重要的是这个区域对于高密度脂蛋白强化HCV进入有关，并且干扰E2中和蛋白与病毒的中合作用。1-13的氨基酸对于HCV进入也无关紧要，但是他们可以通过修饰与SR-BI的吸附来影响HCV感染性。此部位的变异可以导致对于HVR1抗体的抵抗。这些发现使我们对于HCV细胞进入机制和HVR1变异对于HCV免疫逃避的特点有更深刻的了解。对于发展HCV进入抑制剂和预防性疫苗有用。



　　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 comprises 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 (HCVpp) and cell culture- derived HCV (HCVcc) using the H77 isolate indicate that five residues at positions 14, 15and 25-27 mediate binding of the E2 protein to the SR-BI 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 itis involved in heparan binding. More importantly, this region is necessary for the enhancement of HCV entry by high-density lipoprotein (HDL) 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 SR-BI. Mutations occurring at this site may confer resistance to HVR1 antibodies. These findings further our understanding of 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.

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