Car T Cells Encoding alpha-chain-anchored and soluble bnAbs for HIV latency

项目总结 治愈艾滋病毒需要消除携带艾滋病毒前病毒的潜伏感染宿主细胞池， 但事实证明，这相当困难，仍然是该领域的主要障碍。目前，几种化学潜伏期 逆转剂已经被描述过，然而，它们在体内的效果还没有被证明。因此， 迫切需要新的办法来解决这一问题。抗击艾滋病毒的一种有吸引力的方法 潜伏期，将是一种自我维持的治疗方法，可以无休止地监视宿主，迅速杀死新激活的水库 在细胞中释放出大量的病毒。在此之前，T细胞被转导到其表面表达CD4 与激活信号机制相连的表面，嵌合抗原受体(CAR)T细胞被用来 瞄准并杀死受感染的宿主细胞。但这种方法有很大的缺点，包括一部小说 进入途径为感染CD8T细胞，屏蔽了CD4结合部位，缺乏疗效。利用私密的 高亲和力的抗艾滋病毒bNAbs，它们对广泛的艾滋病毒毒株非常有效，联合 凭借卓越的汽车设计，我们在这里建议利用这两个进步来产生加倍的收入 免疫治疗改善了CAR T细胞。这些开创性的研究将为如何 获取和控制潜伏感染艾滋病毒的细胞，并与抗逆转录病毒治疗相结合，解决 艾滋病病毒功能控制的迫切目标。在这个项目完成后，我们预计将有几个验证 CAR T细胞结构为未来在SIV非人类灵长类动物模型和/或人类中进行测试做好了准备。 由于这些研究使用的是自体T细胞，我们预计不良反应很少。此外，如果 成功的、终生使用与毒性有关的抗逆转录病毒药物可能会减少或 也许被这种方法淘汰了。

PROJECT SUMMARY A cure for HIV requires the elimination of the latently-infected pool of host cells harboring HIV provirus, but this has proven quite difficult and remains a major obstacle in the field. Currently, several chemical latency reversing agents have been described, however, their in vivo efficacy has not been demonstrated. Thus, the need for new approaches to address this issue is urgently needed. One attractive method to combat HIV latency, would be a self-sustaining curative to endlessly surveil the host rapidly killing newly activated reservoir cells before the release of a significant amount of virus. Previously, T cells transduced to express CD4 on their surface linked to activation signaling machinery, chimeric antigen receptor (CAR) T cells, were employed to target and kill infected host cells. But there were substantial drawbacks with this approach, including a novel entry route for infection of CD8 T cells, shielding of the CD4-binding site, and lack of efficacy. Utilizing secreted high-affinity anti-HIV bnAbs, which are remarkably effective across a wide swath of HIV strains, in conjunction with superior CAR designs, we here propose to exploit both advancements to generate doubly immunotherapeutic improved CAR T cells. These pioneering studies will provide new insights into how to access and control the reservoir of latently HIV-infected cells and, in combination with ART, address the exigent goal of functional control of HIV. Upon completion of this project, we expect to have several validated CAR T cell constructs ready for future testing in SHIV non-human primate models and/or perhaps humans. Since these studies utilize autologous T cells, we expect to see very few adverse events. Moreover, if successful, life-long use of anti-retrovirals, which have been associated with toxicity, is likely to be reduced or perhaps eliminated by this approach.