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首页> 美国卫生研究院文献>Journal of Virology >Vaccination with a Fusion Protein That Introduces HIV-1 Gag Antigen into a Multitrimer CD40L Construct Results in Enhanced CD8+ T Cell Responses and Protection from Viral Challenge by Vaccinia-Gag
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Vaccination with a Fusion Protein That Introduces HIV-1 Gag Antigen into a Multitrimer CD40L Construct Results in Enhanced CD8+ T Cell Responses and Protection from Viral Challenge by Vaccinia-Gag

机译：将融合HIV-1 Gag抗原引入多三聚体CD40L构建体的融合蛋白进行疫苗接种可增强CD8 + T细胞反应并能抵抗由Vaccinia-Gag引起的病毒攻击

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CD40 ligand (CD40L, CD154) is a membrane protein that is important for the activation of dendritic cells (DCs) and DC-induced CD8+ T cell responses. To be active, CD40L must cluster CD40 receptors on responding cells. To produce a soluble form of CD40L that clusters CD40 receptors necessitates the use of a multitrimer construct. With this in mind, a tripartite fusion protein was made from surfactant protein D (SPD), HIV-1 Gag as a test antigen, and CD40L, where SPD serves as a scaffold for the multitrimer protein complex. This SPD-Gag-CD40L protein activated CD40-bearing cells and bone marrow-derived DCs in vitro. Compared to a plasmid for Gag antigen alone (pGag), DNA vaccination of mice with pSPD-Gag-CD40L induced an increased number of Gag-specific CD8+ T cells with increased avidity for major histocompatibility complex class I-restricted Gag peptide and improved vaccine-induced protection from challenge by vaccinia-Gag virus. The importance of the multitrimeric nature of the complex was shown using a plasmid lacking the N terminus of SPD that produced a single trimer fusion protein. This plasmid, pTrimer-Gag-CD40L, was only weakly active on CD40-bearing cells and did not elicit strong CD8+ T cell responses or improve protection from vaccinia-Gag challenge. An adenovirus 5 (Ad5) vaccine incorporating SPD-Gag-CD40L was much stronger than Ad5 expressing Gag alone (Ad5-Gag) and induced complete protection (i.e., sterilizing immunity) from vaccinia-Gag challenge. Overall, these results show the potential of a new vaccine design in which antigen is introduced into a construct that expresses a multitrimer soluble form of CD40L, leading to strongly protective CD8+ T cell responses.
机译：CD40配体（CD40L，CD154）是一种膜蛋白，对于激活树突状细胞（DC）和DC诱导的CD8 + T细胞反应非常重要。为了活跃，CD40L必须在响应细胞上聚集CD40受体。为了产生聚集CD40受体的CD40L的可溶形式，必须使用多三聚体构建体。考虑到这一点，由表面活性剂蛋白D（SPD），HIV-1 Gag作为测试抗原和CD40L制备了三重融合蛋白，其中SPD充当多三聚体蛋白复合物的支架。这种SPD-Gag-CD40L蛋白在体外激活了带有CD40的细胞和源自骨髓的DC。与单独使用Gag抗原的质粒（pGag）相比，用pSPD-Gag-CD40L的小鼠进行DNA疫苗接种可诱导增加的Gag特异性CD8 + T细胞数量，并且对主要组织相容性复合体I类具有更高的亲和力限制的Gag肽和改进的疫苗诱导的保护，以抵抗牛痘-Gag病毒的攻击。使用缺乏产生单个三聚体融合蛋白的SPD N末端的质粒，显示了复合物多三聚体性质的重要性。该质粒pTrimer-Gag-CD40L仅对带有CD40的细胞具有弱活性，而不会引起强烈的CD8 + T细胞应答或增强对牛痘-Gag攻击的保护作用。掺入SPD-Gag-CD40L的腺病毒5（Ad5）疫苗比单独表达Gag的Ad5（Ad5-Gag）强得多，并诱导了对牛痘-Gag攻击的完全保护（即，杀菌免疫）。总的来说，这些结果表明了一种新疫苗设计的潜力，其中将抗原引入表达CD40L的多三聚体可溶形式的构建体中，从而导致强烈的保护性CD8 + T细胞应答。

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