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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10476697
• 关键词: AIDS clinical trial group; Acute; Address; Agonist; Animals; Antigens; Autopsy; B-Lymphocytes; Bar Codes; Biological Assay; Biological Markers; Blood; Brain; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Maturation; Cell physiology; Cells; Cerebrospinal Fluid; Chronic; Clinical Trials; Clinical assessments; Clonality; Complement; DNA; Data; Disease remission; Dose; Effector Cell; Epigenetic Process; Evaluation; Gene Expression; Generations; Goals; HIV; HIV Infections; Human; Immune; Immunotherapy; In Vitro; Infection; Inflammation; Interleukin-15; Interruption; Intervention; Invaded; Macaca mulatta; Measures; Mediating; Memory; Modeling; Natural Killer Cells; Neuraxis; Neurocognitive; Participant; Pathway interactions; Penetration; Peripheral; Persons; Placebos; Plasma; Population; Residual state; Resistance; Role; SIV; Safety; Sampling; Site; Specificity; T cell response; Techniques; Testing; Thailand; Therapeutic; Time; Tissues; Toxic effect; Viral; Viral Load result; Viral reservoir; acute infection; antiretroviral therapy; arm; blood-brain barrier crossing; brain tissue; cancer therapy; cell type; clinical remission; design; experimental study; immunological intervention; immunoregulation; improved; interest; lymph nodes; migration; multidisciplinary; neuroinflammation; neurotoxicity; nonhuman primate; novel; novel imaging technique; prevent; therapeutic development; tool; trafficking

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

项目摘要 即使在存在抗逆转录病毒疗法（ART）的情况下，艾滋病毒在中枢神经系统（CNS）中长期存在。 针对中枢神经系统中艾滋病毒水库的一种策略是制定旨在增强广度和广度的干预措施 CD8 T细胞的幅度可以穿透并持续在大脑中作为组织驻留细胞。我们的小组有 表明ART时，HIV特异性CD8 T细胞可以限制外围急性感染中的HIV储量 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中的这些细胞 流体（CSF），表明在急性HIV感染期间，在CSF中也可以检测到HIV特异性CD8 T细胞 并在艺术启动后长达2年，在CSF中持续使用。重要的是，这些HIV特异性CD8的存在 T细胞有益于限制神经炎症，但不足以完全消除中枢神经系统中的HIV储藏。 该项目的目的是测试是否通过A进行免疫调节类似于先天性和适应性CD8 T细胞 新型的IL-15超级激动剂（N-803）可以显着降低HIV CNS储层而不会引起神经毒性。 实际上，IL-15促进了HIV特异性CD8 T细胞的强大激活和扩展，并提高了它们的能力 在体外杀死重新激活的HIV储层细胞。 IL-15增强内存CD8 T细胞的产生和持久性 组织以及贩运中枢神经系统。 IL-15还可以促进CD8 T细胞转化为抗原 独立的先天效应细胞，以及NK细胞的激活和膨胀。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，导致血浆病毒载荷减少 并增加了SIV特异性CD8 T细胞向B细胞卵泡的迁移。这些结果支持了 评估IL-15 HIV缓解策略中的IL-15免疫调节潜力。但是，IL-15的潜力 降低中枢神经系统中HIV持续性的免疫疗法仍然未知。在这个项目中，我们将研究影响 在两个人类HIV缓解临床试验中，IL-15的先天性和自适应CD8 T细胞的IL-15。 接收N-803：泰国曼谷的RV550试用 在急性艾滋病毒感染和ACTG A5386试验中，对ART艾滋病毒患者进行了8剂N-803 并接受分析治疗中断。我们还将进行两个NHP实验 两项人类试验的设计将为我们提供尸检时进入脑组织。总的来说，这些 研究允许我们确定急性感染中的N-803是否对CNS安全，并且可以 增强HIV特异性CD8 T细胞介导的中枢神经系统储层的还原。我们还将确定是否 在ART期间给出的N-803的重复给药促进了先天的CD8 T细胞介导的CNS HIV的降低 水库。这些结果应有助于定义CD8 T细胞可以从中清除HIV库中的机制 在免疫调节干预期间，中枢神经系统以及CNS安全，最终可能会告知 开发从中枢神经系统中消除艾滋病毒水库的治疗策略。 1