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

IL-15 免疫疗法对组织特异性 CD8 T 细胞的影响，以减少中枢神经系统 HIV 储存库的播种和持久性

基本信息

批准号：
10476697
负责人：
Lishomwa C Ndhlovu
金额：
$ 116.59万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2023-01-31
项目状态：
已结题

项目摘要

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

项目概要即使在抗逆转录病毒治疗 (ART) 的情况下，艾滋病毒仍会长期存在于中枢神经系统 (CNS) 中。针对中枢神经系统中艾滋病毒储存库的一项策略是制定干预措施，旨在扩大艾滋病毒感染的广度和范围。 CD8 T 细胞的数量，可以作为组织驻留细胞渗透并持续存在于大脑中。我们组有研究表明，当 ART 治疗时，HIV 特异性 CD8 T 细胞可以限制外周急性感染中 HIV 储存库的传播是在急性感染期间开始的。我们开发了独特的工具来分析脑脊髓中的这些细胞脑脊液（CSF），并表明在急性 HIV 感染期间，也可以在 CSF 中检测到 HIV 特异性 CD8 T 细胞并在 ART 开始后在 CSF 中持续长达 2 年。重要的是，这些 HIV 特异性 CD8 的存在 T 细胞有利于限制神经炎症，但不足以完全消除中枢神经系统中的 HIV 病毒库。该项目的目标是测试先天性和适应性 CD8 T 细胞的免疫调节是否通过新型IL-15超级激动剂（N-803）可以显着减少HIV中枢神经系统储存，而不引起神经毒性。事实上，IL-15 可促进 HIV 特异性 CD8 T 细胞的强烈激活和扩增，并提高其体外杀死重新激活的 HIV 储存细胞。 IL-15 增强记忆 CD8 T 细胞的生成和持久性组织以及运输到中枢神经系统。 IL-15还可以促进CD8 T细胞转化为抗原- 独立的先天样效应细胞，以及 NK 细胞的激活和扩增。在非人类灵长类动物中 (NHP)，IL-15 增强了 SIV 特异性 CD8 T 细胞反应的功能，导致血浆病毒载量减少并增加了 SIV 特异性 CD8 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 的潜力减少艾滋病毒在中枢神经系统中持续存在的免疫疗法仍然未知。在这个项目中，我们将研究影响在两项人类 HIV 缓解临床试验中，参与者观察到 IL-15 对先天性和适应性 CD8 T 细胞的影响接受 N-803：在泰国曼谷进行的 RV550 试验，在开始 ART 时给予 3 剂 N-803 急性 HIV 感染期间，以及 ACTG A5386 试验对接受 ART 的 HIV 感染者施用 8 剂 N-803 并接受分析治疗中断。我们还将进行两个 NHP 实验两项人体试验的设计，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在急性感染中使用 N-803 对中枢神经系统是否安全，并且可以增强 HIV 特异性 CD8 T 细胞介导的 CNS 储存库减少。我们还将确定是否 ART 期间重复给予 N-803 有助于先天性 CD8 T 细胞介导的中枢神经系统 HIV 减少水库。这些结果应该有助于确定 CD8 T 细胞清除 HIV 病毒库的机制。免疫调节干预期间的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根除中枢神经系统中艾滋病毒储存库的治疗策略。 1