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: 10677645
• 负责人: Siddappa N Byrareddy
• 金额: $ 89.35万
• 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/10677645
• 关键词: Anti-HIV Agents; Autologous; B-Lymphocytes; BLR1 gene; Basal Ganglia; Binding; Biological Assay; Biological Models; Brain; Brain Stem; Brain region; CAR T cell therapy; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CXCL13 gene; Cells; Cellular immunotherapy; Central Nervous System; Cerebellum; Chronic; Clinical Research; Data; Disease remission; Engineering; Goals; HIV; HIV Infections; Human; Immune; Immunotherapeutic agent; Immunotherapy; In Vitro; Infection; Interruption; Intervention; Location; Lymphoid; Lymphoid Follicle; Lymphoid Tissue; Macaca mulatta; Macrophage; Meninges; Methods; Microglia; Modeling; Myelogenous; Myeloid Cells; Penetration; Peripheral; Persons; Plasma; Population; Productivity; Recrudescences; Research; Rhesus; SIV; Site; Source; Spinal Cord; T cell therapy; T-Lymphocyte; Tissues; Viral; Viral Load result; Viral reservoir; Virus; animal model development; antiretroviral therapy; cell type; cellular targeting; chimeric antigen receptor; chimeric antigen receptor T cells; 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.

HIV治愈已被证明是难以捉摸的，因为HIV在组织庇护所中持续存在，包括HIV感染者（PLWH）的中枢神经系统（CNS）和淋巴滤泡。现在重新出现的数据表明，除了CD 4 T细胞外，髓系细胞是导致组织中HIV持续存在的关键群体，并且是抗逆转录病毒治疗（ART）停止后病毒反弹的主要来源。为了指导有效的治疗策略，需要更好地了解骨髓储库。我们的长期目标是1）了解CNS中骨髓细胞中的HIV/SIV储库，2）开发一种细胞免疫疗法，将病毒特异性嵌合抗原受体（CAR）T细胞靶向CNS和淋巴组织中的HIV组织储库，以持久抑制HIV复制。我们的新数据表明，虽然大多数vRNA+细胞是CD 4 T细胞在慢性SIV感染，分析抗逆转录病毒治疗中断（ATI）后，大多数vRNA+复发细胞可能是骨髓起源的淋巴组织。目前还不清楚什么样的细胞类型会使HIV在ATI后在CNS中复发，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，我们小组目前正在开发一种一次性免疫疗法，用于在没有ART的情况下持久缓解HIV。这种治疗是一种自体HIV特异性CAR（特别是CD 4-MBL-CAR）T细胞疗法，靶向B细胞滤泡，也可能穿透CNS和靶向细胞病毒库。B细胞滤泡和大脑是免疫保护部位，由于病毒特异性CD 8 T细胞水平低，可能允许病毒持续存在。我们将研究CAR-T细胞免疫疗法清除淋巴和CNS储库中CD 4 T细胞和骨髓细胞中SIVmac 251的能力，因为这对于有效的HIV治愈策略至关重要，无论是单独使用还是与其他基于免疫和非免疫疗法的方法联合使用。因此，我们假设淋巴和CNS组织部位中的髓样细胞代表负责病毒复发的主要细胞群体，并且使用表达CXCR 5的工程化CAR T细胞将促进T细胞进入CNS和淋巴滤泡并导致持久缓解。这些开创性的进展将允许开发用于治疗研究的动物模型系统，这些动物模型系统具有挑战性，并且不可能在CNS的人类研究中进行，以便可转化为人类临床研究。具体而言，我们提出1）表征CNS和外周组织中抗逆转录病毒疗法治疗中断（ATI）后SIVmac 251反弹病毒的来源，2）确定CNS中恒河猴CAR/CXCR 5 T细胞的位置、丰度和持久性以及ART释放后它们对SIVmac 251细胞储库的影响，和3）确定恒河猴CAR/CXCR 5 T细胞体外杀伤SIV感染的骨髓细胞的能力。