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

项目总结 即使在抗逆转录病毒疗法(ART)存在的情况下，艾滋病毒仍长期存在于中枢神经系统(CNS)。 针对CNS艾滋病毒宿主的一种战略是开发干预措施，旨在提高广度和 数量巨大的CD8T细胞，它可以作为组织驻留细胞穿透并持续存在于大脑中。我们的团队已经 显示HIV特异性CD8 T细胞可以限制HIV在急性外周感染时的储存播种 是在急性感染期间启动的。我们已经开发了独特的工具来分析脑脊液中的这些细胞 在急性HIV感染期间，脑脊液(CSF)中也可以检测到HIV特异性CD8 T细胞 并在开始治疗后在脑脊液中坚持长达2年。重要的是，这些HIV特异性CD8的存在 T细胞对限制神经炎症是有益的，但还不足以完全消除中枢神经系统中的艾滋病毒蓄积物。 该项目的目标是测试先天类和适应性CD8 T细胞的免疫调节是否通过一种 新型IL-15超级激动剂(N-803)可以显著减少HIV中枢神经系统的储存，而不会造成神经毒性。 事实上，IL-15促进HIV特异性CD8 T细胞的强大激活和扩增，并提高它们的能力 在体外杀死重新激活的HIV储存细胞。IL-15增强小鼠记忆性CD8 T细胞的生成和持续时间 组织以及贩运到中枢神经系统。IL-15还能促进CD8 T细胞向抗原的转化。 独立的先天类效应细胞，以及NK细胞的激活和扩增。在非人类灵长类动物中 (NHP)，IL-15增强SIV特异性CD8 T细胞反应的功能，从而降低血浆病毒载量 促进SIV特异性CD8T细胞向B细胞滤泡的迁移。这些结果支持了 评价IL-15在HIV缓解策略中的免疫调节潜力。然而，IL-15的潜力 减少艾滋病毒在中枢神经系统中持续存在的免疫疗法仍不清楚。在这个项目中，我们将研究其影响 在两项人类HIV缓解临床试验中，IL-15对先天和适应性CD8 T细胞的影响 接受N-803：在泰国曼谷进行的RV550试验，在抗逆转录病毒治疗开始时注射3剂N-803 在急性艾滋病毒感染期间，ACTG A5386试验对接受抗逆转录病毒治疗的艾滋病毒感染者给予8剂N-803 并接受分析治疗中断。我们还将进行两个NHP实验， 这两个人体试验的设计，将为我们提供在尸检时获取脑组织的途径。总而言之，这些 我们的研究使我们能够确定N-803治疗急性感染对中枢神经系统是否安全，以及 增强HIV特异性CD8 T细胞介导的中枢神经系统储备库的减少。我们还将确定是否 抗逆转录病毒治疗期间重复给予N-803促进先天类CD8 T细胞介导的中枢神经系统HIV的减少 水库。这些结果应该有助于确定CD8T细胞清除HIV储备库的机制 在免疫调节干预期间中枢神经系统以及中枢神经系统的安全性，最终可能会告知 制定治疗策略，从中枢神经系统根除艾滋病毒携带者。 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