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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

基本信息

批准号：
10082772
负责人：
Yunlong Huang
金额：
$ 22.95万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10082772
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 Expression Profiling Family Future Gene Expression Glioma Goals Grant 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 mutant neoplastic cell nerve stem cell neuroAIDS novel pre-clinical therapy receptor single cell analysis single cell technology small molecule transcription factor tumor viral rebound

项目摘要

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.

项目概要/摘要尽管采用联合抗逆转录病毒疗法 (ART)，HIV-1 仍继续在淋巴、肠道中形成储存库和中枢神经系统（CNS）。 HIV-1 脑库是一个长寿细胞库，其中包括血管周围巨噬细胞和小胶质细胞可以容纳具有复制能力的病毒。治疗干预迫切需要能够有效消除这些中枢神经系统细胞中的艾滋病毒。 FOXO3a，强大的转录对衰老和免疫稳态至关重要的因素，为消除 HIV-1 病毒库带来了希望。我们之前的出版物已证明 FOXO3a 和细胞因子 TNF 相关凋亡诱导配体 (TRAIL) 靶向 HIV-1 感染的巨噬细胞进行凋亡。有趣的是，明显缺乏 FOXO3a 和 HIV-1 入侵期间 CNS 中的 TRAIL 信号传导。 FOXO3a 信号传导和 TRAIL 表达的缺陷可能会无意中促进 HIV-1 脑储存库的形成。因此，FOXO3a可以作为一种药物目标是在中枢神经系统 HIV-1 感染期间清除 HIV-1 感染的巨噬细胞和小胶质细胞。我们的长期目标是针对 FOXO3a/TRAIL 通路并发现药物以改善人们的治疗感染 HIV-1。我们将利用最近的药物开发，将 ONC201 作为一种有效且有效的药物。 FOXO3a/TRAIL 通路的稳定小分子激活剂。 ONC201具有口服活性，具有较宽的安全范围，并能穿过血脑屏障，具有良好的药代动力学。此外，ONC201还表明在临床前模型中对多种实体瘤和血液恶性肿瘤具有有效的抗肿瘤作用在临床试验中。我们获得了ONC201，并首次证明ONC201具有抗病毒作用体外和小鼠 HIV-1 脑炎模型中（Zhao 等人，抗病毒研究，2019）。此外，我们还有进行了初步研究，证明 ONC201 增强了 ART 药物的抗病毒作用，并且在体外巨噬细胞培养物中延迟病毒反弹。我们假设 FOXO3a 的调节通过一流的抗肿瘤药物 ONC201 将诱导 TRAIL 并促进 ART 从而消除中枢神经系统中的 HIV-1 水库。在目标 1 中，我们将确定 ART 和 ONC201 在人源化治疗中根除 HIV CNS 的效用。 CD34 植入的 IL-34 转基因小鼠作为神经 HIV 模型。在目标 2 中，我们将阐明途径（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 ART 期间与 FOXO3a/TRAIL 的关系。为了实现这些目标，我们将使用“最先进的”人性化小鼠模型和体外巨噬细胞和T细胞培养并评估ONC201和标准品是否 ART可以协同降低中枢神经系统病毒载量并延缓病毒反弹。拟议的研究将提供重要的概念证明，ONC201可以利用内源性FOXO3a来对抗持久性和潜在的 HIV-1 感染。了解 HIV-1 感染的免疫控制与 ART 之间的相互作用将揭示治疗 HIV-1 感染及其中枢神经系统并发症的新见解。