Mukhopadhyay Madhura, Galperin Moran, Patgaonkar Mandar, Vasan Sandhya, Ho David D, Nouël Alexandre, Claireaux Mathieu, Benati Daniela, Lambotte Olivier, Huang Yaoxing, Chakrabarti Lisa A
Institut Pasteur, Unité de Pathogénie Virale, 75724 Paris, France.
INSERM U1108, 75015 Paris, France.
J Immunol. 2017 Nov 15;199(10):3437-3452. doi: 10.4049/jimmunol.1700953. Epub 2017 Oct 9.
Rare patients who spontaneously control HIV replication provide a useful model to inform HIV vaccine development. HIV controllers develop particularly efficient antiviral CD4 T cell responses mediated by shared high-affinity TCRs. To determine whether the candidate DNA vaccine ADVAX could induce similar responses, we analyzed Gag-specific primary CD4 T cells from healthy volunteers who received ADVAX DNA by electroporation. Vaccinated volunteers had an immunodominant response to the Gag293 epitope with a functional avidity intermediate between that of controllers and treated patients. The TCR repertoire of Gag293-specific CD4 T cells proved highly biased, with a predominant usage of the TCRβ variable gene 2 (TRBV2) in vaccinees as well as controllers. TCRα variable gene (TRAV) gene usage was more diverse, with the dominance of TRAV29 over TRAV24 genes in vaccinees, whereas TRAV24 predominated in controllers. Sequence analysis revealed an unexpected degree of overlap between the specific repertoires of vaccinees and controllers, with the sharing of TRAV24 and TRBV2 public motifs (>30%) and of public clonotypes characteristic of high-affinity TCRs. MHC class II tetramer binding revealed a broad HLA-DR cross-restriction, explaining how Gag293-specific public clonotypes could be selected in individuals with diverse genetic backgrounds. TRAV29 clonotypes also proved cross-restricted, but conferred responses of lower functional avidity upon TCR transfer. In conclusion, DNA vaccination by electroporation primed for TCR clonotypes that were associated with HIV control, highlighting the potential of this vaccine delivery method. To our knowledge, this study provides the first proof-of-concept that clonotypic analysis may be used as a tool to monitor the quality of vaccine-induced responses and modulate these toward "controller-like" responses.
极少数能自发控制HIV复制的患者为HIV疫苗研发提供了一个有用的模型。HIV控制者会产生由共享的高亲和力TCR介导的特别有效的抗病毒CD4 T细胞反应。为了确定候选DNA疫苗ADVAX是否能诱导类似的反应，我们分析了通过电穿孔接种ADVAX DNA的健康志愿者的Gag特异性初始CD4 T细胞。接种疫苗的志愿者对Gag293表位有免疫优势反应，其功能亲和力介于控制者和接受治疗的患者之间。Gag293特异性CD4 T细胞的TCR库被证明高度偏向，在疫苗接种者和控制者中主要使用TCRβ可变基因2（TRBV2）。TCRα可变基因（TRAV）的使用更为多样，在疫苗接种者中TRAV29基因比TRAV24基因占优势，而在控制者中TRAV24占主导。序列分析揭示了疫苗接种者和控制者的特定库之间存在意想不到的重叠程度，共享TRAV24和TRBV2公共基序（>30%）以及高亲和力TCR特有的公共克隆型。MHC II类四聚体结合显示出广泛的HLA-DR交叉限制，解释了如何在具有不同遗传背景的个体中选择Gag293特异性公共克隆型。TRAV29克隆型也被证明具有交叉限制，但在TCR转移时产生的功能亲和力反应较低。总之，通过电穿孔进行DNA疫苗接种引发了与HIV控制相关的TCR克隆型，突出了这种疫苗递送方法的潜力。据我们所知，本研究首次提供了概念验证，即克隆型分析可作为一种工具来监测疫苗诱导反应的质量，并将这些反应调节为“类似控制者”的反应。
