CAR T CELLS ENGINEERED TO KILL HIV-INFECTED CELLS WHILE SECRETING BROADLY NEUTRALIZING ANTIBODIES

项目摘要 治愈艾滋病毒需要消除潜伏感染的宿主细胞库， 但这已被证明是相当困难的，并且仍然是该领域的主要障碍。目前，几种化学潜伏 已经描述了逆转剂，然而，它们的体内功效尚未得到证实。因此 迫切需要采取新的办法来解决这一问题。对抗艾滋病毒的一种有吸引力的方法 潜伏期，将是一个自我维持的治疗，无休止地监视主机迅速杀死新激活的水库 在释放大量病毒之前的细胞。以前，T细胞被转导以在其表面表达CD 4。 使用与活化信号传导机制连接的表面嵌合抗原受体（CAR）T细胞， 靶向并杀死受感染的宿主细胞。但这种方法也有很大的缺点，包括一本小说， 感染CD 8 T细胞的进入途径、屏蔽CD 4结合位点和缺乏功效。利用分泌 高亲和力抗HIV bnAb，在广泛的HIV毒株中非常有效， 由于具有上级CAR设计，我们在此建议利用这两种先进技术， 免疫刺激改善了CAR T细胞。这些开创性的研究将为如何 进入和控制潜伏的HIV感染细胞的储存库，并与ART相结合， 艾滋病毒功能控制的迫切目标。在这个项目完成后，我们希望有几个验证 CAR T细胞构建体准备好在SHIV非人灵长类动物模型和/或可能的人类中进行未来测试。 由于这些研究使用自体T细胞，我们预计会看到很少的不良事件。而且如果 抗逆转录病毒药物的成功终生使用可能会减少， 也许会被这种方法消除。

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.