Targeting FOX03a with TIC10 to eradicate HIV-1 from CNS reservoirs

使用 TIC10 靶向 FOX03a 根除 CNS 病毒库中的 HIV-1

• 批准号: 9087368
• 负责人: Yunlong Huang
• 金额: $ 7.53万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9087368
• 关键词: Aging; Antineoplastic Agents; Antiviral Agents; Apoptosis; Apoptotic; Astrocytes; Blood - brain barrier anatomy; Brain; CCL2 gene; Cell Culture Techniques; Cell Nucleus; Cell Survival; Cells; Central Nervous System Infections; Clinical Trials; Drug Targeting; Genes; Genetic Transcription; Goals; HIV; HIV Infections; HIV encephalitis; HIV-1; Homeostasis; Human; Immune; In Vitro; Infection; Inflammation; Interferons; Laboratories; Life; Lymphoid; Lymphoid Tissue; Maintenance; Mediating; Microglia; Modeling; Molecular; Mus; Neuraxis; Neurons; Pharmaceutical Preparations; Publications; Puma; Regulation; Research; Role; SIV; Signal Transduction; TNF gene; TNF-related apoptosis-inducing ligand; Technology; Testing; Therapeutic; Therapeutic Intervention; Transcriptional Regulation; Translations; Up-Regulation; Viral; Viral Load result; Virus; Virus Diseases; Virus Replication; activating transcription factor; antiretroviral therapy; antitumor effect; astrogliosis; combat; cytokine; drug candidate; drug development; humanized mouse; in vivo; insight; macrophage; member; memory CD4 T lymphocyte; mouse model; nerve stem cell; neuroinflammation; novel; novel therapeutics; public health relevance; receptor; small molecule; transcription factor; treatment group

 DESCRIPTION (provided by applicant): 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, available evidence suggests that there is a lack of FOXO3a and TRAIL signaling in the CNS cells during HIV-1 invasion. The deficiency of FOXO3a signaling and TRAIL expression may inadvertently facilitate the forming of HIV-1 brain reservoirs. Because TRAIL expression is under transcription control of FOXO3a, FOXO3a may serve as a drug target to clear HIV-1- infected macrophage and microglia during HIV-1 infection of the CNS. However, targeting FOXO3a in the CNS has not been possible due to a lack of drugs candidates. Recent drug development has provided TIC10, also known as ONC201, as a potent and stable small molecule that can activate FOXO3a and transcriptionally induce TRAIL expression. TIC10 is orally active and can cross blood-brain barrier. Moreover, TIC10 has shown efficacious antitumor effect and is currently tested in clinical trials. Therefore, we hypothesize that targetig transcription factor FOXO3a through TIC10 will induce expression of antiviral gene TRAIL and effectively eradicate HIV-1 reservoirs in the CNS. We will determine the functional effects of TIC10-mediated FOXO3a activation on HIV-1-infected macrophages and microglia. Furthermore, we will assess the therapeutic benefit of TIC10-mediated FOXO3a activation toward CNS viral load and neuroinflammation in HIV encephalitis (HIVE) and humanized mouse models. More importantly, we will determine whether the TIC10 has synergistic antiviral effect with the standard ART both in vitro and in vivo. The proposed studies will provide important proof-of-concept that endogenous FOXO3a could be harnessed to combat persistent and latent HIV-1 infection. The research strategy takes advantage of the latest drug development, the primary CNS cell cultures, the laboratory and primary live HIV-1 viral strains, and the technologies of HIVE and humanized mouse models. Understanding the interactions between immune control of HIV-1 infection and current ART will reveal new insights for the treatment of HIV-1 infection and its CNS complications.

 描述（由应用提供）：尽管结合了抗逆转录病毒疗法（ART），HI​​V-1仍在淋巴机，肠道和中枢神经系统（CNS）中形成储层。 HIV-1脑部储层是一组长寿命的细胞，其中包括血管周围巨噬细胞和可携带复制性病毒的小胶质细胞。迫切需要在这些中枢神经系统细胞中有效消除HIV的治疗干预措施。 FOXO3A是对衰老和免疫体内平衡至关重要的有力转录因子，它提供了消除HIV-1储层的希望。我们以前的出版物表明，FOXO3A和细胞因子与TNF相关的凋亡诱导的配体（TRAIL）靶向HIV-1感染的巨噬细胞用于凋亡。有趣的是，可用的证据表明，HIV-1入侵期间CNS细胞中缺乏FOXO3A和TRAIL信号传导。 FOXO3A信号传导和跟踪表达的缺乏可能会无意间支持HIV-1脑储层的形成。由于TRAIL表达在FOXO3A的转录控制下，因此FOXO3A可以作为CNS HIV-1感染期间清除HIV-1感染巨噬细胞和小胶质细胞的药物靶标。但是，由于缺乏候选药物，因此不可能在中枢神经系统中瞄准FOXO3A。最近的药物开发提供了TIC10，也称为ONC201，是一种潜在稳定的小分子，可以激活FoxO3A并转录诱导步道表达。 TIC10是口服的，可以跨越血脑屏障。此外，TIC10已显示出有效的抗肿瘤作用，目前已在临床试验中进行了测试。因此，我们假设通过TIC10的靶标转录因子FOXO3A将诱导抗病毒基因径径的表达，并有效地在中枢神经系统中放射性地抑制HIV-1储存剂。我们将确定TIC10介导的FOXO3A激活对HIV-1感染的巨噬细胞和小胶质细胞的功能作用。此外，我们将评估TIC10介导的FOXO3A激活对HIV脑炎（HIVE）和人源化小鼠模型中CNS病毒载荷和神经炎症的治疗益处。更重要的是，我们将确定TIC10在体外和体内是否具有与标准艺术的协同抗病毒作用。拟议的研究将提供重要的概念证明，即可以利用内源性FOXO3A来应对持续和潜在的HIV-1感染。研究策略利用了最新的药物开发，主要的CNS细胞培养物，实验室和原发性HIV-1病毒株以及蜂巢和人源化小鼠模型的技术。了解HIV-1感染与当前ART的免疫控制之间的相互作用将揭示用于治疗HIV-1感染及其中枢神经系统并发症的新见解。

项目成果

Direct conversion of mouse astrocytes into neural progenitor cells and specific lineages of neurons.

• DOI: 10.1186/s40035-018-0132-x
• 发表时间: 2018
• 期刊: Translational neurodegeneration
• 影响因子: 12.6
• 作者: Ma K;Deng X;Xia X;Fan Z;Qi X;Wang Y;Li Y;Ma Y;Chen Q;Peng H;Ding J;Li C;Huang Y;Tian C;Zheng JC
• 通讯作者: Zheng JC

Glutaminase 1 regulates the release of extracellular vesicles during neuroinflammation through key metabolic intermediate alpha-ketoglutarate.

• DOI: 10.1186/s12974-018-1120-x
• 发表时间: 2018-03-14
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3
• 作者: Wu B;Liu J;Zhao R;Li Y;Peer J;Braun AL;Zhao L;Wang Y;Tong Z;Huang Y;Zheng JC
• 通讯作者: Zheng JC