Targeting HIV-specific CAR T cells to the gut for the durable remission of HIV

将 HIV 特异性 CAR T 细胞靶向肠道以实现 HIV 的持久缓解

基本信息

批准号：
10527172
负责人：
PAMELA J SKINNER
金额：
$ 74.37万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10527172
关键词：
Animals Anti-Retroviral Agents Antiviral Agents Area Autologous B-Lymphocytes Biological Response Modifiers CCR9 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cells Combined Modality Therapy Control Animal Data Disease remission Goals Gut associated lymphoid tissue HIV HIV Infections HIV therapy HIV-1 Homing Human Human immunodeficiency virus test Immunotherapy In Vitro Individual Infection Interruption Intervention Intestinal Mucosa Intestines Location Longevity Lymphoid Follicle Lymphoid Tissue Macaca Macaca mulatta Methods Mucous Membrane Myeloid Cells Persons Pharmacotherapy Phenotype RNA SIV Source T cell response T-Lymphocyte Testing Time Tissues Viral Viral Load result Viral Physiology Viral reservoir Viremia Virus Virus Replication Work anti-viral efficacy antiretroviral therapy chimeric antigen receptor T cells chronic infection combinatorial engineered T cells in vivo lymph nodes migration nonhuman primate novel therapeutics viral RNA viral rebound

项目摘要

Abstract Virus-specific CD8 T cells exert potent antiviral activity against HIV-1 and SIV. Despite abundant CD8 T cell responses, these are unable to fully suppress virus replication. This is likely due to the majority of viral replication occurring in CD4+ T cells concentrated in specific areas in the body, such as B-cell follicles in secondary lymphoid tissues and in intestinal tissues. Viral reservoir studies indicate that the majority of SIV and HIV replication may occur in the intestinal mucosa: After ART interruption, the location, abundance, and phenotype of recrudescing virally infected cells are not well understood. However, emerging data suggest that both CD4 T cells, as well as myeloid cells, in lymph node (LN) and the intestine are important contributors. Thus, there is a need to develop methods to reduce viral load in mucosal tissues, as well as in LN, and to more fully understand the source of viral reservoirs in non-lymphoid tissues. CAR T cells can be potent mediators of immune control and these are being explored as an HIV therapy. We have developed and begun testing an HIV/SIV targeting CAR. In this study, we have developed and propose to test autologous T cells engineered to express the HIV-targeting CAR and CCR9, a molecule that will target cells to the intestinal mucosa. We will test our hypothesis that targeting HIV-specific T cells to the intestinal mucosa, as well as B cell follicles, will lead to durable remission of HIV. We propose two aims to test the hypothesis. Aim 1: to determine the in vivo localization, persistence and antiviral efficacy and impact on intestinal mucosa, lymphoid tissue, and other tissue viral reservoirs in SIV infected ART suppressed rhesus macaques infused with autologous CAR/CCR9 T cells. Aim 2: to determine whether combination therapy using both intestine- and lymphoid follicle-homing CAR T cells is superior in promoting sustained remission of SIV after antiretroviral drug treatment interruption. If successful, this work may lead to an immunotherapy that leads to long-term suppression of HIV.

抽象的病毒特异性 CD8 T 细胞对 HIV-1 和 SIV 发挥有效的抗病毒活性。尽管丰富 CD8 T细胞反应，这些都无法完全抑制病毒复制。这可能是由于大多数病毒复制发生在 CD4+ T 细胞中，集中在特定区域身体，例如次级淋巴组织和肠道组织中的 B 细胞滤泡。病毒性的储存库研究表明，大多数 SIV 和 HIV 复制可能发生在肠道中粘膜：ART 中断后，病毒复发的位置、丰度和表型受感染的细胞尚不清楚。然而，新出现的数据表明 CD4 T 细胞，与骨髓细胞一样，淋巴结 (LN) 和肠道中的细胞也是重要的贡献者。因此，需要开发方法来减少粘膜组织以及淋巴结中的病毒载量，并更全面地了解非淋巴组织中病毒库的来源。 CAR-T细胞可能是免疫控制的有效介质，并且正在将其作为艾滋病毒疗法进行探索。我们已经开发并开始测试针对 HIV/SIV 的 CAR。在这项研究中，我们开发了并提议测试经工程设计以表达 HIV 靶向 CAR 和 CCR9 的自体 T 细胞，一种将细胞靶向肠粘膜的分子。我们将检验我们的假设将 HIV 特异性 T 细胞靶向肠粘膜以及 B 细胞滤泡，将导致 HIV 的持久缓解。我们提出两个目标来检验该假设。目标 1：确定体内定位、持久性和抗病毒功效以及对肠粘膜、淋巴的影响感染 SIV 的 ART 抑制的恒河猴体内的组织和其他组织病毒库注入自体 CAR/CCR9 T 细胞。目标2：确定是否联合治疗使用肠道和淋巴滤泡归巢 CAR T 细胞在促进抗逆转录病毒药物治疗中断后 SIV 持续缓解。如果成功的话，这项工作可能会导致免疫疗法，从而长期抑制艾滋病毒。