Role of pannexin-1 hemichannels in NeuroAIDS

pannexin-1 半通道在 NeuroAIDS 中的作用

• 批准号: 9271671
• 负责人: Eliseo A Eugenin
• 金额: $ 72.01万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9271671
• 关键词: AIDS Dementia Complex; Address; Adverse effects; Animal Model; Binding; Biological Markers; Brain; CCR5 gene; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; CXCR4 gene; Cell Adhesion Molecules; Cells; Central Nervous System Diseases; Central Nervous System Infections; Cognition Disorders; Cytoplasm; Data; Disease; Electrophysiology (science); Ethnic Origin; Ethnic group; Extracellular Space; Functional disorder; Genetic Polymorphism; Goals; HIV; HIV Infections; HIV Receptors; HIV-1; Human; Image; Immune; Immune system; Impaired cognition; In Vitro; Individual; Infection; Infiltration; Inflammation; Inflammatory; Integration Host Factors; Ion Channel; Ischemia; Laboratories; Leukocytes; Life Cycle Stages; Link; Mediating; Modeling; Molecular; Monkeys; Nervous System Trauma; Neurologic; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Peripheral; Persons; Pharmacology; Phenotype; Physiological; Predisposition; Prostaglandins; Proteins; Purinoceptor; Regulation; Reperfusion Therapy; Reporting; Role; SIV; Sampling; Serum; Signaling Molecule; Stroke; Study models; Surface; Testing; Therapeutic Intervention; Time; Variant; Viral; Viral Load result; Virus Diseases; Virus Replication; base; channel blockers; chemokine; design; differential expression; experimental study; humanized mouse; in vivo; interdisciplinary approach; macrophage; monocyte; neuroAIDS; neuroinflammation; peptidomimetics; prevent; receptor; receptor expression; release factor; response; therapeutic target; trafficking

Project Abstract: According to WHO and UN reports, in 2014 an estimated 34 million persons worldwide were living with HIV. In addition to compromising the immune system, HIV can also infect the CNS early during the disease, leading to devastating neurological consequences (NeuroAIDS). A growing body of evidence indicates that neurological damage in NeuroAIDS is triggered not by the active viral replication but by the transmigration of HIV-infected leukocytes into the brain and the associated neuroinflammation. While it is well established that HIV uses host-encoded proteins to facilitate viral infection, replication and transmigration into the CNS, specific host factors involved in the pathogenesis of NeuroAIDS are still extremely poorly understood. Our laboratory recently identified pannexin-1 channels as essential components of the HIV life cycle in immune cells as well as in the pathogenesis of NeuroAIDS. In particular, we and others have demonstrated that pannexin-1 channel opening facilitates multiple steps of HIV-mediated CNS compromise, including: (1) regulation of CCR5 surface aggregation and trafficking in response to HIV infection; (2) HIV entry by direct regulation of the channel opening and subsequent release of intracellular ATP, auto-activating purinergic receptors; (3) release of intracellular factors such as ATP that promote inflammation; (4) monocyte differentiation and maturation in response to chemokines and/or HIV; (5) increased expression of several adhesion molecules required for leukocytes to transmigrate across the BBB; (6) neuroinflammation. We also found that ATP compromises BBB integrity and function, and our analysis of a large number of patient samples suggests that circulating ATP may be a biomarker of CNS disease. Our preliminary data indicate that different ethnic groups carry specific pannexin-1 polymorphisms and have differential expression and opening of this channel, potentially underlying, at least in part, the observed variation in susceptibility to HIV infection and NeuroAIDS among different ethnicities. Our recent preliminary data indicate that circulating ATP concentrations and their correlation with CNS compromise are also ethnicity related. Importantly, pannexin-1 channels have excellent potential as a therapeutic target because (1) their opening can be effectively blocked in vivo using several pannexin-1 channel blockers, including a specific mimetic peptide we recently designed; and (2) these channels mostly exist in a closed state under physiological conditions, minimizing potential side effects. This proposal is designed to define the mechanisms linking pannexin-1 channel opening to HIV receptor expression, trafficking, and function (Aim 1), leukocyte differentiation and transmigration into the CNS (Aim 2), and the role of neuroinflammatory factors released through the channel in BBB and CNS function (Aim 3). Finally, in Aim 4 we will examine the role of pannexin-1 channels in two animal models. Together, these experiments will reveal the role of an important new host factor in NeuroAIDS.

项目摘要： 根据世卫组织和联合国的报告，2014年，全球估计有3400万人患有 艾滋病。除了损害免疫系统外，HIV还可以在感染早期感染CNS。 疾病，导致毁灭性的神经后果（神经艾滋病）。越来越多的证据 表明NeuroAIDS的神经损伤不是由活跃的病毒复制引发的，而是由 HIV感染的白细胞向大脑的迁移以及相关的神经炎症。虽然 众所周知，HIV使用宿主编码的蛋白质来促进病毒感染、复制和 尽管神经艾滋病的发病机制中涉及的特异性宿主因子已经迁移到CNS中，但仍存在一些问题。 非常不了解。我们的实验室最近确定泛连接蛋白-1通道是必不可少的 免疫细胞中的HIV生命周期的组成部分以及NeuroAIDS的发病机制。在 特别是，我们和其他人已经证明，泛连接蛋白-1通道开放促进了多个步骤， HIV介导的中枢神经系统损害，包括：（1）调节CCR 5表面聚集和运输， 对HIV感染的反应;（2）HIV通过直接调节通道开放进入， 释放细胞内ATP，自动激活嘌呤能受体;（3）释放细胞内因子， 促进炎症的ATP;（4）单核细胞分化和成熟对趋化因子的反应 和/或HIV;（5）白细胞粘附所需的几种粘附分子的表达增加， （6）神经炎症。我们还发现ATP会损害血脑屏障的完整性 和功能，我们对大量患者样本的分析表明，循环ATP可能是 CNS疾病的生物标志物。我们的初步数据表明，不同的种族群体携带特定的 泛连接蛋白-1多态性，并有差异表达和开放这一通道，可能 这至少部分地解释了观察到的艾滋病毒感染和神经艾滋病易感性的变化， 不同的种族我们最近的初步数据表明，循环ATP浓度及其 与CNS损害的相关性也与种族有关。重要的是，泛连接蛋白-1通道具有 作为治疗靶点的优异潜力，因为（1）它们的开放可以在体内有效地阻断 使用几种泛连接蛋白-1通道阻断剂，包括我们最近设计的一种特异性模拟肽; 以及（2）这些通道在生理条件下大多以闭合状态存在， 副作用.该提议旨在定义连接泛连接蛋白-1通道开放与 HIV受体表达、运输和功能（目标1），白细胞分化和迁移到 中枢神经系统（目的2），以及通过通道释放的神经炎症因子在BBB和 CNS功能（目标3）。最后，在目标4中，我们将研究泛连接蛋白-1通道在两种动物中的作用。 模型总之，这些实验将揭示一个重要的新宿主因子在神经艾滋病中的作用。