Impact of IL-15 immunotherapy on tissue-specific CD8 T cells to reduce the CNS HIV reservoir seeding and persistence

项目摘要 HIV在中枢神经系统（CNS）中长期存在，即使在抗逆转录病毒治疗（ART）的情况下。 针对中枢神经系统中艾滋病毒储库的一项战略是制定干预措施，旨在提高 CD 8 T细胞的数量级，其可以作为组织驻留细胞渗透并持续存在于脑中。我们集团 显示HIV特异性CD 8 T细胞可以限制ART时外周急性感染中的HIV储库接种， 是在急性感染时开始的。我们已经开发了独特的工具来分析这些细胞在脑脊髓 结果表明，在急性HIV感染期间，也可以在CSF中检测到HIV特异性CD 8 T细胞 并且在ART开始后在CSF中持续长达2年。重要的是，这些HIV特异性CD 8 T细胞有益于限制神经炎症，但不足以完全消除CNS中的HIV储库。 本项目的目标是测试是否通过免疫调节先天性和适应性CD 8 T细胞， 新型IL-15超激动剂（N-803）可显著减少HIV CNS储库而不引起神经毒性。 事实上，IL-15促进HIV特异性CD 8 T细胞的强烈活化和扩增，并提高其免疫应答的能力。 杀死体外重新激活的HIV储库细胞。IL-15增强记忆性CD 8 T细胞的产生和持久性， 组织以及运输到CNS。IL-15还可以促进CD 8 T细胞转化为抗原-T细胞。 独立的先天样效应细胞，以及NK细胞的活化和扩增。在非人类灵长类动物中 (NHP)IL-15增强了SIV特异性CD 8 T细胞应答的功能，导致血浆病毒载量降低 并增加SIV特异性CD 8 T细胞向B细胞滤泡的迁移。这些结果支持了 评估IL-15在HIV缓解策略中的免疫调节潜力。然而，IL-15的潜力 减少HIV在CNS中持续存在的免疫疗法仍然未知。在这个项目中，我们将研究 在两项人类HIV缓解临床试验中，IL-15对先天性和适应性CD 8 T细胞的作用， 接受N-803：在泰国曼谷进行的RV 550试验，在ART开始时给予3剂N-803 在急性HIV感染期间，以及ACTG A5386试验在接受ART的HIV感染者中给予8剂N-803 并中断了分析治疗我们还将进行两个NHP实验， 两个人体试验的设计，这将使我们能够在尸检时接触到脑组织。总的来说，这些 研究使我们能够确定N-803在急性感染中的给药是否对CNS安全， 增强HIV特异性CD 8 T细胞介导的CNS储库减少。我们还将确定 ART期间重复给予N-803促进先天性CD 8 T细胞介导的CNS HIV减少 水库这些结果应该有助于确定CD 8 T细胞可以清除HIV储库的机制。 CNS以及免疫调节干预期间的CNS安全性，最终可能会影响 开发治疗策略以从CNS中根除HIV储库。 1

PROJECT SUMMARY HIV persists long-term in the central nervous system (CNS) even in the presence of antiretroviral therapy (ART). One strategy to target HIV reservoirs in the CNS is to develop interventions aimed at enhancing the breadth and magnitude of CD8 T cells, which can penetrate and persist in the brain as tissue resident cells. Our group has shown that HIV-specific CD8 T cells can limit HIV reservoir seeding in acute infection in the periphery when ART is initiated during acute infection. We have developed unique tools to analyze these cells in the cerebrospinal fluid (CSF) and showed that HIV-specific CD8 T cells can also be detected in the CSF during acute HIV infection and persist in the CSF for up to 2 years after ART initiation. Importantly, the presence of these HIV-specific CD8 T cells is beneficial for limiting neuroinflammation but not enough to fully eliminate HIV reservoirs in the CNS. The goal of this project is to test whether the immunomodulation of innate-like and adaptive CD8 T cells via a novel IL-15 super-agonist (N-803) can significantly reduce HIV CNS reservoirs without causing neurotoxicity. Indeed, IL-15 promotes strong activation and expansion of HIV-specific CD8 T cells and improves their ability to kill reactivated HIV reservoir cells in vitro. IL-15 enhances memory CD8 T cell generation and persistence in tissues as well as trafficking to the CNS. IL-15 can also promote the conversion of CD8 T cells into antigen- independent innate-like effector cells, as well as the activation and expansion of NK cells. In nonhuman primates (NHP), IL-15 enhanced the function of SIV-specific CD8 T cell responses resulting in reduced plasma viral loads and increased the migration of SIV-specific CD8 T cells to B cell follicles. These results have supported the evaluation of IL-15 immunomodulatory potential in HIV remission strategies. However, the potential for IL-15 immunotherapy to reduce HIV persistence in the CNS remains unknown. In this project, we will study the impact of IL-15 on innate-like and adaptive CD8 T cells in two human HIV remission clinical trials in which participants receive N-803: the RV550 trial in Bangkok, Thailand, administering 3 doses of N-803 at time of ART initiation during acute HIV infection, and the ACTG A5386 trial administering 8 doses of N-803 in people with HIV on ART and undergoing an analytic treatment interruption. We will also conduct two NHP experiments following the design of the two human trials, that will provide us with access to brain tissue at necropsy. Collectively, these studies we allow us to determine whether N-803 administration in acute infection is safe for the CNS and can enhance HIV-specific CD8 T cell-mediated reduction of the CNS reservoirs. We will also determine whether repeated dosing of N-803 given during ART facilitates innate-like CD8 T cell-mediated reduction of CNS HIV reservoirs. These results should help define mechanisms by which CD8 T cells can clear HIV reservoirs from the CNS as well as CNS safety during an immunomodulatory intervention that may ultimately inform on the development of therapeutic strategies to eradicate the HIV reservoirs from the CNS. 1