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.

项目概要 高效抗逆转录病毒疗法（ART；HAART）在抑制 HIV 方面取得了巨大成功 复制并降低艾滋病毒相关的发病率和死亡率。然而，与艾滋病毒相关的流行病 神经性疼痛和神经认知缺陷等神经系统疾病（神经艾滋病）的发病率仍然很高，即使在 后艺术时代。从低病毒载量的角度来看，这是令人费解的，并提出了重大的临床挑战。 然而，人们对潜在的神经病理生理学机制知之甚少。新出现的证据表明 持续的慢性神经炎症在神经艾滋病发病机制中的关键作用。目前的机制研究 重点关注 HIV-1 有毒蛋白（例如 gp120 和 Tat）引发神经炎症的过程。然而，鉴于低 ART 后的病毒载量，蛋白质的致病意义仍不确定。由于艾滋病毒患者需要 如果长期接受 ART，我们认为测试替代可能性在临床上很重要：抗- 逆转录病毒疗法本身会引起神经炎症反应，尽管它将 HIV 病毒载量控制在较低水平 水平并抑制病毒引起的免疫反应。这种假设的治疗诱发慢性 神经炎症如果得到验证，可能会对未来 ART 治疗方案的设计产生深远的影响。在这个 研究中，我们将重点关注药物在当前 ART 中的潜在参与，尤其是其支柱 成分 - 核苷逆转录酶抑制剂（NRTI）。基于大量的初步数据，我们 假设 NRTI 通过以下机制对慢性神经炎症产生重要影响： 涉及 Wnt5a 上调。具体来说，我们的假设表明 NRTI 会导致 Wnt5a 增加 中枢神经系统，然后刺激星形胶质细胞表达促炎因子。慢性增加 炎症介质预计会引起神经艾滋病相关的神经元损伤。为了检验这个假设，我们 将表征 NRTI 诱导的中枢神经系统神经炎症（目标 1），阐明 NRTI 的机制 诱导的 CNS 神经炎症（目标 2），并确定 NRTI 诱导的 CNS 的病理生理作用 病理性疼痛发展中的神经炎症（目标 3）。成功完成这些概念性工作 创新研究将显着增进我们对神经病理机制的理解 NRTIs/ART 可能会导致 HIV 患者的神经系统疾病。新的发现可能会导致进一步 临床环境中 ART 的优化以及 ART 佐剂的开发以预防 NeuroAIDS，例如 慢性疼痛和认知缺陷。