Botten Jason, Whitton J Lindsay, Barrowman Polly, Sidney John, Whitmire Jason K, Alexander Jeff, Ting Joey P C, Bui Huynh-Hoa, Sette Alessandro, Buchmeier Michael J
Molecular and Integrative Neurosciences Department, The Scripps Research Institute, SP30-2020, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
J Virol. 2007 Mar;81(5):2307-17. doi: 10.1128/JVI.02063-06. Epub 2006 Dec 13.
The consequences of human lymphocytic choriomeningitis virus (LCMV) infection can be severe, including aseptic meningitis in immunocompetent individuals, hydrocephalus or chorioretinitis in fetal infection, or a highly lethal outcome in immunosuppressed individuals. In murine models of LCMV infection, CD8(+) T cells play a primary role in providing protective immunity, and there is evidence that cellular immunity may also be important in related arenavirus infections in humans. For this reason, we sought to identify HLA-A2 supertype-restricted epitopes from the LCMV proteome and evaluate them as vaccine determinants in HLA transgenic mice. We identified four HLA-A0201-restricted peptides-nucleoprotein NP(69-77), glycoprotein precursor GPC(10-18), GPC(447-455), and zinc-binding protein Z(49-58)-that displayed high-affinity binding (< or =275 nM) to HLA-A0201, induced CD8(+) T-cell responses of high functional avidity in HLA-A0201 transgenic mice, and were naturally processed from native LCMV antigens in HLA-restricted human antigen presenting cells. One of the epitopes (GPC(447-455)), after peptide immunization of HLA-A0201 mice, induced CD8(+) T cells capable of killing peptide-pulsed HLA-A*0201-restricted target cells in vivo and protected mice against lethal intracranial challenge with LCMV.
人类淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染的后果可能很严重，包括免疫功能正常个体发生无菌性脑膜炎、胎儿感染时出现脑积水或脉络膜视网膜炎，或免疫抑制个体出现高度致死性结局。在LCMV感染的小鼠模型中，CD8(+) T细胞在提供保护性免疫方面起主要作用，并且有证据表明细胞免疫在人类相关沙粒病毒感染中也可能很重要。因此，我们试图从LCMV蛋白质组中鉴定HLA - A2超型限制性表位，并在HLA转基因小鼠中评估它们作为疫苗决定簇的作用。我们鉴定出四种HLA - A0201限制性肽——核蛋白NP(69 - 77)、糖蛋白前体GPC(10 - 18)、GPC(447 - 455)和锌结合蛋白Z(49 - 58)——它们与HLA - A0201表现出高亲和力结合（≤275 nM），在HLA - A0201转基因小鼠中诱导出高功能亲和力的CD8(+) T细胞反应，并且在HLA限制性人类抗原呈递细胞中从天然LCMV抗原中自然加工产生。其中一个表位（GPC(447 - 455)）在对HLA - A0201小鼠进行肽免疫后，诱导出能够在体内杀死肽脉冲的HLA - A*0201限制性靶细胞的CD8(+) T细胞，并保护小鼠免受LCMV致死性颅内攻击。
