Eradication of CNS HIV reservoirs through a first-in-class anti-tumor agent ONC201

通过一流的抗肿瘤药物 ONC201 根除 CNS HIV 储存库

• 批准号: 10202458
• 负责人: Yunlong Huang
• 金额: $ 19.13万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202458
• 关键词: AKT inhibition; Advanced Malignant Neoplasm; Aging; Antiviral Agents; Apoptosis; Astrocytes; Blood - brain barrier anatomy; Brain; CD34 gene; Cell Culture System; Cell Culture Techniques; Cell Nucleus; Cell Survival; Cells; Central Nervous System Infections; Clinical Data; Clinical Trials; Control Groups; Data; Drug Kinetics; Drug Targeting; Encephalitis; Family; Future; Gene Expression; Glioma; Goals; Grant; H3 K27M mutation; HIV; HIV-1; Hematologic Neoplasms; Homeostasis; Human; Immune; In Vitro; Infection; Laboratories; Lymphoid; Lymphoid Tissue; MAPK3 gene; Maintenance; Mediating; Microglia; Modeling; Modification; Molecular; Mus; Neuraxis; Neurons; Normal Cell; Oral; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Plasma; Pre-Clinical Model; Principal Component Analysis; Publications; Recurrence; Regimen; Research; Safety; Signal Transduction; Site; Solid Neoplasm; T-Lymphocyte; TNF gene; TNF-related apoptosis-inducing ligand; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Toxic effect; Transgenic Mice; Transgenic Model; Transgenic Organisms; United States National Institutes of Health; Up-Regulation; Viral; Viral Load result; Virus; activating transcription factor; antiretroviral therapy; antitumor agent; antitumor drug; antitumor effect; biological adaptation to stress; cancer clinical trial; cell type; combat; cytokine; drug development; drug discovery; humanized mouse; immunoregulation; improved; insight; latent HIV reservoir; macrophage; memory CD4 T lymphocyte; mouse model; neoplastic cell; nerve stem cell; neuroAIDS; novel; pre-clinical therapy; receptor; single cell analysis; single cell technology; small molecule; transcription factor; tumor; viral rebound

Project Summary/Abstract Despite combination antiretroviral therapy (ART), HIV-1 continues to form reservoirs in lymphoid, gut and central nervous system (CNS). The HIV-1 brain reservoir is a pool of long-lived cells, which include perivascular macrophages and microglia that can harbor replication-competent virus. Therapeutic interventions that can effectively eliminate HIV in these CNS cells are urgently needed. FOXO3a, a powerful transcription factor critical for aging and immune homeostasis, offers hope to eliminate HIV-1 reservoirs. Our previous publications have demonstrated that FOXO3a and cytokine TNF-related apoptosis-inducing ligand (TRAIL) target HIV-1-infected macrophages for apoptosis. Interestingly, there is an apparent lack of FOXO3a and TRAIL signaling in the CNS during HIV-1 invasion. The deficiency of FOXO3a signaling and TRAIL expression may inadvertently facilitate the forming of HIV-1 brain reservoirs. Therefore, FOXO3a may serve as a drug target to clear HIV-1-infected macrophage and microglia during HIV-1 infection of the CNS. Our long-term objective is to target FOXO3a/TRAIL pathway and make drug discoveries to improve treatment for people living with HIV-1. We will take advantage of a recent drug development that provided ONC201 as a potent and stable small molecule activator of FOXO3a/TRAIL pathway. ONC201 is orally active, has a wide safety margin, and can cross the blood-brain barrier with favorable pharmacokinetics. Moreover, ONC201 has shown efficacious antitumor effect in numerous solid tumors and hematological malignancies in preclinical models and in clinical trials. We have obtained ONC201 and shown for the first time that ONC201 has anti-viral effects in vitro and in a murine HIV-1 encephalitis model (Zhao et al, Antiviral Research, 2019). Furthermore, we have performed preliminary studies demonstrating that ONC201 potentiates the anti-viral effect of ART drug and delays viral rebound in vitro in macrophage cultures. We hypothesize that modulation of FOXO3a through the first-in-class anti-tumor drug ONC201 will induce TRAIL and facilitate ART leading to HIV-1 elimination in CNS reservoirs. In Aim 1, we will determine the utility of ART and ONC201 in HIV CNS eradication in the humanized CD34-engrafted IL-34-transgenic mice as a model for neuroHIV. In Aim 2, we will elucidate the pathways (mechanisms) responsible for ONC201-mediated viral clearance in macrophages, microglia, and T cells in relation to FOXO3a/TRAIL during ART. To achieve these aims, we will use a “state of the art” humanized mouse model and in vitro macrophage and T cell cultures and evaluate whether ONC201 and the standard ART can synergistically reduce the CNS viral load and delay viral rebound. The proposed studies will provide important proof-of-concept that endogenous FOXO3a could be harnessed by ONC201 to combat persistent and latent HIV-1 infection. Understanding the interactions between immune control of HIV-1 infection and ART will reveal new insights for the treatment of HIV-1 infection and its CNS complications.

项目摘要/摘要 尽管联合抗逆转录病毒疗法(ART)，HIV-1继续在淋巴、肠道内形成储存库 和中枢神经系统(CNS)。HIV-1大脑储备库是一个长寿命细胞池，其中包括 血管周围巨噬细胞和小胶质细胞可以携带复制能力强的病毒。治疗性干预 能够有效清除这些中枢神经系统细胞中的艾滋病毒是迫切需要的。FOXO3a，一个强大的转录工具 对衰老和免疫动态平衡至关重要的因素，为消除艾滋病毒-1宿主提供了希望。我们以前的 已有文献证明FOXO3a和细胞因子肿瘤坏死因子相关的凋亡诱导配体(TRAIL) 靶向HIV-1感染的巨噬细胞进行细胞凋亡。有趣的是，FOXO3a和 HIV-1入侵期间中枢神经系统中的TRAIL信号转导。FOXO3a信号转导和TRAIL表达的缺陷 可能在不经意间促进了HIV-1脑部蓄水池的形成。因此，FOXO3a可以作为一种药物 目的：在HIV-1感染中枢神经系统的过程中清除感染HIV-1的巨噬细胞和小胶质细胞。我们的长期合作 目的是针对FOXO3a/TRAIL途径并进行药物发现，以改善人们的治疗 与HIV-1一起生活。我们将利用最近的药物开发，提供ONC201作为一种有效和 稳定的FOXO3a/TRAIL途径小分子激活剂。ONC201具有口服活性，具有广泛的安全边际， 并能通过血脑屏障，具有良好的药代动力学。此外，ONC201已经显示出 在临床前模型和模型中对许多实体瘤和血液系统恶性肿瘤的有效抗肿瘤作用 在临床试验中。我们已经获得了ONC201，并首次表明ONC201具有抗病毒作用 在体外和小鼠HIV-1脑炎模型中(赵等人，抗病毒研究，2019年)。此外，我们还拥有 进行的初步研究表明，ONC201增强了抗逆转录病毒药物和 在巨噬细胞培养中延缓病毒体外反弹。我们假设FOXO3a的调制是通过 一流抗肿瘤药物ONC201将诱导TRAIL并促进ART在中枢神经系统消除HIV-1 水库。在目标1中，我们将确定ART和ONC201在人性化人群中根除HIV CNS的效用 移植CD34的IL-34转基因小鼠作为神经性HIV的模型。在目标2中，我们将阐明这些途径 (机制)负责ONC201介导的巨噬细胞、小胶质细胞和T细胞中的病毒清除 在ART期间与FOXO3a/TRAIL的关系。为了实现这些目标，我们将用一种人性化的“艺术状态” 小鼠模型及巨噬细胞和T细胞的体外培养，并评价ONC201和标准 ART可协同降低CNS病毒载量，延缓病毒反弹。拟议的研究将提供 内源性FOXO3a可被ONC201利用来对抗持续性的重要概念证明 和潜伏的HIV-1感染。了解HIV-1感染的免疫控制与抗逆转录病毒治疗的相互作用 将为HIV-1感染及其中枢神经系统并发症的治疗提供新的见解。