Antiretroviral Therapy and Neuroinflammation in the CNS

抗逆转录病毒治疗和中枢神经系统神经炎症

• 批准号: 9271670
• 负责人: SHAO-JUN TANG
• 金额: $ 52.69万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9271670
• 关键词: Adjuvant; Adult; Anti-Retroviral Agents; Astrocytes; Chronic; Clinical; Cognitive deficits; Complication; Data; Development; Future; HIV; HIV Envelope Protein gp120; HIV-1; Highly Active Antiretroviral Therapy; Hippocampus (Brain); Immune response; Immunoblotting; Inflammation Mediators; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Interleukin-1 beta; Investigation; Knock-out; Knockout Mice; Lamivudine; Lead; Life; Measures; Mediating; Microglia; Morbidity - disease rate; Mus; Neurocognitive Deficit; Neuroglia; Neurons; Nucleosides; Pain; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Prevalence; Proteins; Regimen; Reverse Transcriptase Inhibitors; Role; Signal Transduction; Signaling Protein; Source; Spinal Cord; TNF gene; Testing; Time; Up-Regulation; Vertebral column; Viral Load result; Virus; Work; Zalcitabine; Zidovudine; antiretroviral therapy; astrogliosis; base; chronic pain; cytokine; design; genetic approach; glial activation; innovation; insight; mortality; nervous system disorder; neuroAIDS; neuroinflammation; non-nucleoside reverse transcriptase inhibitors; painful neuropathy; prevent; response; success

PROJECT SUMMARY Highly active anti-retroviral therapy (ART; HAART) has had tremendous success in suppressing HIV replication and reducing HIV-associated morbidity and mortality. However, the prevalence of HIV-associated neurological disorders (NeuroAIDS) such as neuropathic pain and neurocognitive deficits remain high, even in the post ART era. This is puzzling in the perspective of low viral loads, and presents major clinical challenges. Yet, the underlying neuropathophysiological mechanism is poorly understood. Emerging evidence suggests a key role of ongoing chronic neuroinflammation in NeuroAIDS pathogenesis. Current mechanistic investigation focuses on HIV-1 toxic proteins such as gp120 and Tat in eliciting neuroinflammation. However, given the low viral loads after ART, the pathogenic significance of the proteins remains uncertain. Since HIV patients need to stay on ART for a long time, we reason that it is clinically important to test the alternative possibility: anti- retroviral therapy itself evokes neuroinflammatory responses, even though it controls HIV viral loads at a low level and suppresses virus-induced immune responses. This hypothesized therapy-induced chronic neuroinflammation, if validated, may have a profound impact on the design of future ART regimens. In this study, we will focus on the potential involvement of drugs in the current ART, especially its backbone components - nucleoside reverse transcriptase inhibitors (NRTIs). Based on extensive preliminary data, we hypothesize that NRTIs critically contribute to the chronic neuroinflammation through a mechanism that involves Wnt5a up-regulation. Specifically, our hypothesis entails that NRTIs cause Wnt5a increase in the CNS, which then stimulates astrocytes to express pro-inflammatory factors. Chronic increase of the inflammatory mediators is expected to cause NeuroAIDS-related neuronal damage. To test this hypothesis, we will characterize NRTI-induced neuroinflammation in the CNS (Aim 1), elucidate the mechanism of NRTI- induced CNS neuroinflammation (Aim 2), and determine the pathophysiological role of NRTI-induced CNS neuroinflammation in pathological pain development (Aim 3). Successful completion of these conceptually innovative studies will significantly advance our understanding of the neuropathogenic mechanisms by which NRTIs/ART may contribute to neurological disorders in HIV patients. The new findings may lead to further optimization of ART in clinical settings and the development of ART adjuvants to prevent NeuroAIDS, such as chronic pain and cognitive deficits.

项目摘要 高度活跃的抗逆转录病毒疗法（ART; HAART）在抑制HIV方面取得了巨大成功 复制并降低与HIV相关的发病率和死亡率。但是，与HIV相关的患病率 神经系统疾病（神经助理），例如神经性疼痛和神经认知缺陷，即使在 后艺术时代。从低病毒负荷的角度来看，这令人困惑，并带来了主要的临床挑战。 然而，基本的神经病理生理机制知之甚少。新兴证据表明 持续的慢性神经炎症在神经辅助发病机理中的关键作用。当前的机械调查 专注于引起神经炎症的HIV-1有毒蛋白，例如GP120和TAT。但是，鉴于低 艺术后的病毒载荷，蛋白质的致病意义仍然不确定。由于艾滋病毒患者需要 长期保持艺术，我们认为测试替代可能性在临床上很重要：反 - 逆转录病毒疗法本身会唤起神经炎症反应，即使它控制着低的HIV病毒负荷 水平并抑制病毒诱导的免疫反应。这种假设的治疗引起的慢性 神经炎症（如果得到验证）可能会对未来艺术方案的设计产生深远的影响。在这个 研究，我们将专注于药物在当前艺术中的潜在参与，尤其是其骨干 成分 - 核苷逆转录酶抑制剂（NRTIS）。基于广泛的初步数据，我们 假设NRTI通过一种机制批判性地有助于慢性神经炎症 涉及WNT5A上调。具体而言，我们的假设需要NRTI导致Wnt5a的增加 CNS，然后刺激星形胶质细胞表达促炎性因子。慢性增长 预计炎症介质会导致与神经相关的神经元损害。为了检验这一假设，我们 将表征NRTI诱导的中枢神经系统神经炎症（AIM 1），阐明了NRTI-的机制 诱导CNS神经炎症（AIM 2），并确定NRTI诱导的CNS的病理生理作用 病理疼痛发育中的神经炎症（AIM 3）。这些概念上成功完成了这些 创新的研究将大大提高我们对神经病机制的理解 NRTIS/ART可能会导致HIV患者的神经系统疾病。新发现可能会进一步 在临床环境中优化艺术和艺术佐剂的发展，以防止神经辅助 慢性疼痛和认知缺陷。