Antiretroviral Therapy and Neuroinflammation in the CNS

项目摘要 高效抗逆转录病毒疗法（ART; HAART）在抑制艾滋病毒方面取得了巨大成功 减少艾滋病毒相关的发病率和死亡率。然而，与艾滋病毒相关的 神经系统疾病（NeuroAIDS），如神经性疼痛和神经认知缺陷仍然很高，即使在 后艺术时代从低病毒载量的角度来看，这是令人困惑的，并提出了重大的临床挑战。 然而，潜在的神经病理生理机制知之甚少。新出现的证据表明， 持续慢性神经炎症在NeuroAIDS发病机制中的关键作用。当前的机理研究 重点关注HIV-1毒性蛋白如gp 120和达特在引发神经炎症中的作用。然而，由于低 尽管ART后的病毒载量增加，但蛋白质的致病意义仍不确定。由于艾滋病患者需要 长期接受抗逆转录病毒治疗，我们认为在临床上测试替代的可能性是很重要的： 逆转录病毒疗法本身引起神经炎症反应，即使它将HIV病毒载量控制在较低水平， 水平和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ART方案的设计产生深远的影响。在这 在这项研究中，我们将重点关注药物在当前ART中的潜在参与，特别是其骨干 成分-核苷逆转录酶抑制剂（NRTI）。根据大量的初步数据，我们 假设NRTI通过一种机制， 涉及Wnt 5a上调。具体地说，我们的假设是NRTI导致Wnt 5a增加， CNS，然后刺激星形胶质细胞表达促炎因子。长期增加的 预期炎性介质会引起神经AIDS相关的神经元损伤。为了验证这个假设，我们 将描述NRTI诱导的CNS神经炎症（目的1），阐明NRTI的机制， 诱导的CNS神经炎症（目的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（目的3）。成功完成这些概念 创新的研究将大大推进我们对神经致病机制的理解， NRTIs/ART可能导致HIV患者的神经系统疾病。新的发现可能会导致进一步的 在临床环境中优化ART，开发ART佐剂以预防NeuroAIDS，如 慢性疼痛和认知缺陷。

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.