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（由申请人提供）：尽管进行了联合抗逆转录病毒治疗（ART），HI​​V-1 仍继续在淋巴、肠道和中枢神经系统（CNS）中形成储存库。 HIV-1脑库是一个长寿细胞池，其中包括血管周围巨噬细胞和小胶质细胞，它们可以容纳具有复制能力的病毒。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的治疗干预措施。 FOXO3a 是一种对衰老和免疫稳态至关重要的强大转录因子，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，现有证据表明，在 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 TRAIL 表达的缺陷可能会无意中促进 HIV-1 脑储存库的形成。由于 TRAIL 表达受到 FOXO3a 转录控制，因此 FOXO3a 可以作为药物靶标，在 HIV-1 感染 CNS 期间清除 HIV-1 感染的巨噬细胞和小胶质细胞。然而，由于缺乏候选药物，靶向中枢神经系统中的 FOXO3a 尚不可能。最近的药物开发提供了 TIC10（也称为 ONC201）作为一种有效且稳定的小分子，可以激活 FOXO3a 并转录诱导 TRAIL 表达。 TIC10 具有口服活性，可以穿过血脑屏障。此外，TIC10已显示出有效的抗肿瘤作用，目前正在临床试验中进行测试。因此，我们假设通过TIC10靶向转录因子FOXO3a将诱导抗病毒基因TRAIL的表达并有效根除中枢神经系统中的HIV-1储存库。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影响。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 病毒载量和神经炎症的治疗益处。更重要的是，我们将确定TIC10在体外和体内是否与标准ART具有协同抗病毒作用。拟议的研究将提供重要的概念证明，即内源性 FOXO3a 可用于对抗持续和潜在的 HIV-1 感染。该研究策略利用了最新的药物开发、原代中枢神经系统细胞培养物、实验室和原代活HIV-1病毒株以及HIVE和人源化小鼠模型的技术。了解 HIV-1 感染的免疫控制与当前 ART 之间的相互作用将为治疗 HIV-1 感染及其中枢神经系统并发症提供新的见解。

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