Unité d'Immunité Cellulaire Antivirale, Département d'Immunologie, Institut Pasteur, 25 rue du Dr Roux, Paris Cedex 15, France.
AIDS. 2009 Sep 24;23(15):1945-54. doi: 10.1097/QAD.0b013e32832fae88.
To design a vaccine construct containing various but conserved HIV-1-derived epitopes and generating broad CD8 T cell responses.
HLA-B7 transgenic H-2KD KO transgenic mice were used to identify potential new HLA-B07.02-restricted HIV-1-derived epitopes. Immunological recognition of these epitopes was confirmed by IFN-gamma ELISpot assays with PBMCs from HLA-B*0702 HIV-1-infected individuals. For these peptides as well as others previously identified, the capacity to induce cross-reactive responses against their frequent allelic variants was evaluated in the mouse model. A set of epitopes inducing strong T cell responses against various and conserved regions of HIV-1 was selected. A DNA vaccine was designed to express them as a unique antigen with or without a three amino acid ARY extension flanking each epitope. The spectrum of CD8 T responses generated by polyepitope constructs was tested in HLA-B7 transgenic mice.
Five new epitopes were identified in accessory and regulatory HIV-1 proteins. Twelve HLA-B07.02-restricted epitopes were selected on the basis of their structural conservation and cross-reactive immunogenicity. The ARY N-terminal extension flanking each epitope markedly increases their affinity for TAP and the use of this flanking extension in polyepitope vaccine has a sizable advantage to induce CD8 T cell cytotoxic responses in mice following DNA immunization.
The HLA-B7 mouse model allows to rapidly identify various HIV-1-derived epitopes of vaccine interest. Grouped in a polyepitope construct designed to increase their processing, this vaccine may be suitable for inducing multiple and relevant HIV-1-specific CTL responses in humans.
设计一种包含各种但保守的 HIV-1 衍生表位的疫苗构建体，产生广泛的 CD8 T 细胞反应。
使用 HLA-B7 转基因 H-2KD KO 转基因小鼠来鉴定潜在的新的 HLA-B07.02 限制的 HIV-1 衍生表位。通过 IFN-γ ELISpot 测定与 HLA-B*0702 HIV-1 感染个体的 PBMC 确认这些表位的免疫识别。对于这些肽以及其他先前鉴定的肽，在小鼠模型中评估了诱导针对其频繁等位基因变异体的交叉反应性应答的能力。选择了一组诱导针对 HIV-1 的各种保守区域的强 T 细胞反应的表位。设计了一种 DNA 疫苗，以表达它们作为具有或不具有侧翼每个表位的三个氨基酸 ARY 延伸的独特抗原。在 HLA-B7 转基因小鼠中测试了多表位构建体产生的 CD8 T 反应谱。
在辅助和调节 HIV-1 蛋白中鉴定了五个新表位。基于其结构保守性和交叉免疫原性，选择了 12 个 HLA-B07.02 限制的表位。侧翼每个表位的 ARY N 末端延伸显著增加了它们对 TAP 的亲和力，并且在多表位疫苗中使用这种侧翼延伸在 DNA 免疫后在小鼠中诱导 CD8 T 细胞细胞毒性反应具有相当大的优势。
HLA-B7 小鼠模型允许快速鉴定各种具有疫苗兴趣的 HIV-1 衍生表位。在设计为增加其加工的多表位构建体中分组，该疫苗可适用于诱导人类中多种相关的 HIV-1 特异性 CTL 反应。
