Targeting CNS reservoirs with CAR/CXCR5 T cells for the long-term remission of HIV

使用 CAR/CXCR5 T 细胞靶向 CNS 储存库以长期缓解 HIV

• 批准号: 10475466
• 负责人: Siddappa N Byrareddy
• 金额: $ 92.98万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10475466
• 关键词: Anti-HIV Agents; Autologous; B-Lymphocytes; BLR1 gene; Basal Ganglia; Biological Assay; Biological Models; Brain; Brain Stem; Brain region; CAR T cell therapy; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; CXCL13 gene; Cells; Cellular immunotherapy; Cerebellum; Chronic; Clinical Research; Data; Disease remission; Engineering; Goals; HIV; HIV Infections; Human; Immune; Immunotherapeutic agent; Immunotherapy; In Vitro; Infection; Interruption; Intervention; Lead; Location; Lymphoid; Lymphoid Follicle; Lymphoid Tissue; Meninges; Methods; Microglia; Modeling; Myelogenous; Myeloid Cells; Neuraxis; Peripheral; Persons; Plasma; Population; Recrudescences; Research; Rhesus; SIV; Site; Source; Spinal Cord; T cell therapy; T-Lymphocyte; Time; Tissues; Viral; Viral Load result; Viral reservoir; Virus; animal model development; antiretroviral therapy; base; cell type; cellular targeting; chimeric antigen receptor; chimeric antigen receptor T cells; macrophage; next generation; nonhuman primate; targeted treatment; viral rebound

HIV cure has proven elusive given the persistence of HIV in tissue sanctuaries including the central nervous system (CNS) and lymphoid follicles in people living with HIV (PLWH). Re-emerging data now indicate that myeloid cells in addition to CD4 T cells represent a key population contributing to HIV persistence in tissues and are a major source of viral rebound after antiretroviral therapy (ART) cessation. A better understanding of myeloid reservoirs are needed in order to guide effective cure strategies. Our long-term goals are to 1) understand HIV/SIV reservoirs in myeloid cells in the CNS, and 2) develop a cellular immunotherapy that targets virus-specific chimeric antigen receptor (CAR) T cells to tissue reservoirs of HIV in the CNS and lymphoid tissues to durably suppress HIV replication. Our emerging data suggests that whilst most vRNA+ cells are CD4 T cells during chronic SIV infections, after analytical antiretroviral treatment interruption (ATI), the majority of vRNA+ recrudescing cells may be of myeloid origin in lymphoid tissues. It is unknown what cell types recrudesce HIV post-ATI in the CNS and this will be crucial if we are to have successful remission. In order to achieve sustained HIV remission our group is currently developing a one-time immunotherapeutic for durable remission of HIV in the absence of ART. This treatment is an autologous HIV-specific CAR (specifically CD4-MBL-CAR) T-cell therapy that targets B cell follicles, and may also penetrate the CNS and target cellular viral reservoirs. B cell follicles and the brain are immune protected sites that may permit viral persistence due to low levels of virus-specific CD8 T cells. We will investigate the capacity of CAR-T-cell immunotherapy to clear SIVmac251 in both CD4 T cells and myeloid cells in lymphoid and CNS reservoirs as this will be crucial for an effective HIV cure strategy either alone or in combination with other immuno and non-immunotherapy based approaches in humans. Therefore we hypothesize that myeloid cells in lymphoid and CNS tissue sites represent the predominant cell population responsible for viral recrudescence and using engineered CAR T cells that express CXCR5 will facilitate T-cell egress into both the CNS and lymphoid follicles and lead to durable remission. These pioneering advances will permit the development of animal model systems for cure research that are challenging and impossible to perform in human studies of the CNS for translatability to human clinical studies. Specifically, we propose to 1) To characterize the source of SIVmac251 rebound virus post-antiretroviral therapy treatment interruption (ATI) in the CNS and peripheral tissues, 2) To determine the location, abundance, and persistence of rhesus CAR/CXCR5 T cells in the CNS and their impact on SIVmac251 cellular reservoirs post ART release, and 3) To determine the ability of rhesus CAR/CXCR5 T cells to kill SIV infected myeloid cells in vitro.

鉴于艾滋病毒在艾滋病毒（PLWH）患者中，包括中枢神经系统（CNS）（CNS）和淋巴卵泡在内的艾滋病毒持续存在，艾滋病毒治愈已被证明是难以捉摸的。重新出现的数据现在表明，除了CD4 T细胞外，髓样细胞代表了有助于组织中HIV持续性的关键种群，并且是抗逆转录病毒治疗（ART）戒断后病毒反弹的主要来源。为了指导有效的治疗策略，需要更好地了解髓样储层。我们的长期目标是1）了解中枢神经系统中髓样细胞中的HIV/SIV储量，以及2）发展一种细胞免疫疗法，将病毒特异性嵌合抗原受体（CAR）T细胞靶向CNS和CNS和淋巴组织中HIV的组织储存剂，以持久抑制HIV HIV HEIV HEV。我们的新兴数据表明，尽管大多数VRNA+细胞是慢性SIV感染期间的CD4 T细胞，但在分析抗逆转录病毒治疗中断（ATI）之后（ATI），大多数VRNA+饲养细胞可能是淋巴机构中髓样的起源。中枢神经系统中ATI的细胞类型引起了哪些细胞类型，如果我们要成功缓解，这将是至关重要的。为了实现持续的HIV缓解，我们的小组目前正在开发一种一次性免疫治疗，以在没有艺术的情况下持久缓解HIV。该治疗方法是一种靶向B细胞卵泡的自体HIV特异性CAR（特别是CD4-MBL）T细胞疗法，也可能穿透CNS和靶标细胞病毒储层。 B细胞卵泡和大脑是免疫保护的部位，由于病毒特异性CD8 T细胞的水平较低，可能允许病毒持久性。我们将研究CAR-T细胞免疫疗法清除淋巴样和CNS储层中CD4 T细胞和髓样细胞中SIVMAC251的能力，因为这对于单独或与其他免疫和非免疫疗法结合的有效HIV治疗策略至关重要。因此，我们假设淋巴样和中枢神经系统组织部位的髓样细胞代表了负责病毒复发的主要细胞群体，并使用表达CXCR5的工程CAR T细胞将促进T-Cell出口到中枢神经系统和淋巴样卵泡中，并导致耐用的缓解。这些开创性的进步将允许开发动物模型系统，用于治疗研究，这些系统具有挑战性，在人力研究中无法进行人类研究，以转换为人类的临床研究。具体而言，我们建议1）表征SIVMAC251反弹病毒的抗逆转录病毒治疗后治疗中断（ATI）中断（ATI）（ATI）（ATI）（ATI）（ATI）（2），2）确定位置，丰富性和持续性的位置，丰富性和持续性，以确定CNS及其对CNS的影响，并确定其对CNS的影响，并确定Sivmac251 Cellir sivmac251 Cell sivmac251 cill sivmac251 cyl sivmac251 cell sivmac251 cyl sivmac251 cyl sivmac251 cyl sivmac25 1在体外杀死SIV感染的髓样细胞的恒河猴/CXCR5 T细胞的体外。