Genetically Modified NKT Cells to Target Viral Reservoirs

项目摘要 尽管长期给予有效的病毒抑制性抗逆转录病毒治疗（ART），但艾滋病毒仍持续存在 仍然是艾滋病毒根除和治疗的主要障碍。免疫工具，如基因 具有嵌合抗原受体（CAR）的修饰的T细胞提供了一种新的且潜在有前途的体内方法 专门针对并杀死感染艾滋病毒的细胞。这项提案的目标是通过基因工程抗艾滋病毒 汽车针对不变的自然杀伤T（NKT）细胞，目的是利用CAR的免疫抑制潜力。 这种独特的先天性T细胞亚群靶向组织储库部位的HIV感染细胞。我们的具体目标是： SA #1。为了评估当用NKT转导时猕猴NKT细胞的体外扩增、信号传导和CTL活性， 含有Tc特异性胞内信号传导结构域的CD 4-CAR载体（NKT-CAR）;和SA#2。为了评价 过继转移的抗HIV NKT-CAR和对照Tc-CAR的体内生物分布和持久性 SHIV感染前后的猕猴。

PROJECT SUMMARY HIV persistence despite long-term administration of potent viral-suppressive antiretroviral therapy (ART) remains a major impediment to HIV eradication and cure. Immunotherapeutic tools such as genetically modified T cells with chimeric antigen receptors (CAR) offer a new and potentially promising in vivo approach to specifically target and kill HIV-infected cells. The goal of this proposal is to genetically engineer anti-HIV CARs to invariant natural killer T (NKT) cells, with the aim of harnessing the immunotherapeutic potential of this unique innate T cell subset to target HIV-infected cells at tissue reservoir sites. Our specific aims are: SA#1. To evaluate in vitro expansion, signaling, and CTL activity of macaque NKT cells when transduced with CD4-CAR vectors containing Tc-specific intracellular signaling domains (NKT-CAR); and SA#2. To evaluate in vivo biodistribution, and persistence of adoptively transferred anti-HIV NKT-CARs and control Tc-CARs in macaques before and after SHIV infection.