Novel Identified HLA-A*0201-Restricted Hantaan Virus Glycoprotein Cytotoxic T-Cell Epitopes Could Effectively Induce Protective Responses in HLA-A2.1/K(b) Transgenic Mice May Associate with the Severity of Hemorrhagic Fever with Renal Syndrome.
Novel Identified HLA-A*0201-Restricted Hantaan Virus Glycoprotein Cytotoxic T-Cell Epitopes Could Effectively Induce Protective Responses in HLA-A2.1/K(b) Transgenic Mice May Associate with the Severity of Hemorrhagic Fever with Renal Syndrome.
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DOI：
10.3389/fimmu.2017.01797
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发表时间：
2017
影响因子：
7.3
通讯作者：
Ma Y
中科院分区：
文献类型：
--
作者：
Tang K;Cheng L;Zhang C;Zhang Y;Zheng X;Zhang Y;Zhuang R;Jin B;Zhang F;Ma Y
汉滩病毒(HTNV)感染可导致严重的肾综合征出血热(HFRS)，这与高病死率有关。细胞毒性T细胞(CTL)应答有助于病毒的清除；然而，迄今为止，CTL识别的人类白细胞抗原I类等位基因限制性HTNV糖蛋白(GP)表位尚未见报道，这限制了我们对人类抗HTNV感染的CTL应答的了解。在这项研究中，使用BIMAS和SYFPEITHI数据库预测了34个HTNV gp九聚体表位，这些表位可能与HLA-A*0201分子结合。T2细胞结合实验证明其中7个表位能与人类白细胞抗原A*0201分子高亲和力结合，并成功地用于合成肽/人类白细胞抗原A*0201四聚体。四聚体染色结果显示，轻度肾综合征出血热患者各表位特异性CTL的频率较高，提示这些表位可能在HTNV感染后诱导保护性CTL应答。干扰素-γ-酶联免疫斑点分析通过激发抗原表位特异性的干扰素-γ产生的CTL反应进一步证实了表位的免疫反应性。在HTNV攻击试验中，预先接种非肽VV9(aa8-aa16，VMASLVWPV)、SL9(a996-aa1004，SLTECPTFL)和LL9(aa358-aa366，LIWTGMIDL)的HLA-A2.1/KB转基因小鼠的主要靶器官(肝、脾和肾)的HTNV复制受到显著抑制。重要的是，LL9表现出最好的诱导保护性CTL反应的能力，并对肾脏显示出显著的作用，潜在地预防HTNV感染后的肾脏损伤。综上所述，我们的结果强调了HTNV gp衍生的人类白细胞抗原-A*0201限制性表位可以诱导针对该病毒的保护性CTL反应，而LL9表位作为免疫优势的保护性表位可能促进安全有效的基于CTL的人类HTNV多肽疫苗的设计。
Hantaan virus (HTNV) infections can cause severe hemorrhagic fever with renal syndrome (HFRS) in humans, which is associated with high fatality rates. Cytotoxic T cell (CTL) responses contribute to virus elimination; however, to date, HLA class I allele-restricted HTNV glycoprotein (GP) epitopes recognized by CTLs have not been reported, limiting our understanding of CTL responses against HTNV infection in humans. In this study, 34 HTNV GP nine-mer epitopes that may bind to HLA-A*0201 molecules were predicted using the BIMAS and SYFPEITHI database. Seven of the epitopes were demonstrated to bind to HLA-A*0201 molecules with high affinity via the T2 cell binding assay and were successfully used to synthesize peptide/HLA-A*0201 tetramers. The results of tetramer staining showed that the frequencies of each epitope-specific CTL were higher in patients with milder HFRS, which indicated that the epitopes may induce protective CTL responses after HTNV infection. IFN-γ-enzyme-linked immunospot analysis further confirmed the immunoreactivity of epitopes by eliciting epitope-specific IFN-γ-producing CTL responses. In an HTNV challenge trial, significant inhibition of HTNV replication characterized by lower levels of antigens and RNA loads was observed in major target organs (liver, spleen, and kidneys) of HLA-A2.1/Kb transgenic mice pre-vaccinated with nonapeptides VV9 (aa8–aa16, VMASLVWPV), SL9 (aa996–aa1004, SLTECPTFL) and LL9 (aa358–aa366, LIWTGMIDL). Importantly, LL9 exhibited the best ability to induce protective CTL responses and showed a prominent effect on the kidneys, potentially preventing kidney injury after HTNV infection. Taken together, our results highlight that HTNV GP-derived HLA-A*0201-restricted epitopes could elicit protective CTL responses against the virus, and that epitope LL9 functions as an immunodominant protective epitope that may advance the design of safe and effective CTL-based HTNV peptide vaccines for humans.
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影响因子：
3.8
作者：
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