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Design of TLR2-ligand-synthetic long peptide conjugates for therapeutic vaccination of chronic HBV patients.

设计用于慢性 HBV 患者治疗性疫苗接种的 TLR2-ligand-synthetic 长肽结合物。

  • 影响因子:4.19
  • DOI:10.1016/j.antiviral.2020.104746
  • 作者列表:"Dou Y","Jansen DTSL","van den Bosch A","de Man RA","van Montfoort N","Araman C","van Kasteren SI","Zom GG","Krebber WJ","Melief CJM","Woltman AM","Buschow SI
  • 发表时间:2020-02-17
Abstract

:Synthetic long peptide (SLP) vaccination is a promising new treatment strategy for patients with a chronic hepatitis B virus (HBV) infection. We have previously shown that a prototype HBV-core protein derived SLP was capable of boosting CD4+ and CD8+ T cell responses in the presence of a TLR2-ligand in chronic HBV patients ex vivo. For optimal efficacy of a therapeutic vaccine in vivo, adjuvants can be conjugated to the SLP to ensure delivery of both the antigen and the co-stimulatory signal to the same antigen-presenting cell (APC). Dendritic cells (DCs) express the receptor for the adjuvant and are optimally equipped to efficiently process and present the SLP-contained epitopes to T cells. Here, we investigated TLR2-ligand conjugation of the prototype HBV-core SLP. Results indicated that TLR2-ligand conjugation reduced cross-presentation efficiency of the SLP-contained epitope by both monocyte-derived and naturally occurring DC subsets. Importantly, cross-presentation was improved after optimization of the conjugate by either shortening the SLP or by placing a valine-citrulline linker between the TLR2-ligand and the long SLP, to facilitate endosomal dissociation of SLP and TLR2-ligand after uptake. HBV-core SLP conjugates also triggered functional patient T cell responses ex vivo. These results provide an import step forward in the design of a therapeutic SLP-based vaccine to cure chronic HBV.

摘要

: 合成长肽 (SLP) 疫苗接种是慢性乙型肝炎病毒 (HBV) 感染患者的一种有前途的新治疗策略。我们以前已经证明,一个原型 HBV 核心蛋白衍生的 SLP 能够促进 CD4 + 和 CD8 + T 细胞反应在慢性 HBV 患者离体 TLR2-ligand 的存在。为了在体内获得治疗性疫苗的最佳疗效, 佐剂可以与 SLP 偶联,以确保将抗原和共刺激信号递送到同一抗原呈递细胞 (APC)。树突状细胞 (DCs) 表达佐剂的受体,并具有最佳的条件,可有效处理含 SLP 的表位并将其呈递给 T 细胞。在这里,我们研究了原型 HBV 核心 SLP 的 TLR2-ligand 接合。结果表明,TLR2-ligand 接合降低了单核细胞来源和天然存在的 DC 亚群对含 SLP 表位的交叉呈递效率。重要的是,在优化结合物后,通过缩短 SLP 或在 TLR2-ligand 和长 SLP 之间放置缬氨酸-瓜氨酸接头,改善了交叉呈递。促进 SLP 和 TLR2-ligand 摄取后的内体解离。HBV 核心 SLP 结合物也触发功能性患者离体 T 细胞反应。这些结果为设计治疗性 SLP 疫苗治疗慢性 HBV 提供了一个重要的步骤。

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作者列表:["Chen VL","Chen Y","Du X","Handelman SK","Speliotes EK"]

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影响因子:2.57
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DOI:10.1111/eci.13198
作者列表:["Li H","Wieser A","Zhang J","Liss I","Markwardt D","Hornung R","Neumann-Cip AC","Mayerle J","Gerbes A","Steib CJ"]

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