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

项目总结/摘要 尽管联合抗逆转录病毒治疗（ART），HIV-1继续在淋巴，肠道和淋巴细胞中形成储库。 中枢神经系统（CNS）。HIV-1的大脑储存库是一个长寿细胞库，其中包括 血管周围的巨噬细胞和小胶质细胞，可以窝藏复制能力的病毒。治疗干预 能够有效地消除这些CNS细胞中的HIV的方法是迫切需要的。FOXO 3a，一个强大的转录 对衰老和免疫稳态至关重要的因素，为消除HIV-1储存库提供了希望。我们以前的 已经有出版物证明FOXO 3a和细胞因子TNF-相关凋亡诱导配体（TRAIL） 靶向HIV-1感染巨噬细胞进行凋亡。有趣的是，明显缺乏FOXO 3a， HIV-1侵袭期间CNS中的TRAIL信号传导。FOXO 3a信号转导和TRAIL表达的缺陷 可能无意中促进了HIV-1脑储库的形成。因此，FOXO 3a可以作为药物 靶向清除HIV-1感染CNS期间HIV-1感染的巨噬细胞和小胶质细胞。我们的长期 目的是靶向FOXO 3a/TRAIL通路，并发现药物以改善人们的治疗 HIV-1感染者我们将利用最近的药物开发，提供ONC 201作为一种有效的， FOXO 3a/TRAIL途径稳定小分子激活剂。ONC 201具有口服活性，具有较宽的安全范围， 并且可以以有利的药代动力学穿过血脑屏障。此外，ONC 201显示 在临床前模型中对许多实体瘤和血液恶性肿瘤具有有效的抗肿瘤作用， 在临床试验阶段我们已经获得了ONC 201，并首次显示ONC 201在人结肠癌中具有抗病毒作用。 体外和鼠HIV-1脑炎模型（Zhao et al，Antiviral Research，2019）。此外，我们有 进行了初步研究，证明ONC 201增强了ART药物的抗病毒作用， 在体外巨噬细胞培养中延迟病毒反弹。我们假设FOXO 3a的调节是通过 第一种抗肿瘤药物ONC 201将诱导TRAIL并促进ART，导致CNS中的HIV-1消除 水库在目标1中，我们将确定ART和ONC 201在人源化的人源 移植了CD 34的IL-34转基因小鼠作为neuroHIV的模型。在目标2中，我们将阐明 （机制）负责ONC 201介导的巨噬细胞，小胶质细胞和T细胞中的病毒清除， 为了实现这些目标，我们将使用一种“最先进的”人源化的 小鼠模型和体外巨噬细胞和T细胞培养物，并评估ONC 201和标准品 ART可以协同降低CNS病毒载量并延迟病毒反弹。拟议的研究将提供 内源性FOXO 3a可以被ONC 201利用来对抗持续性的 和潜伏的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。

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.