Antiretroviral Therapy and Neuroinflammation in the CNS

项目总结 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 复制和减少艾滋病毒相关的发病率和死亡率。然而，与艾滋病毒相关的流行率 神经疾病(神经艾滋病)，如神经病理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，这是令人费解的，并提出了重大的临床挑战。 然而，其潜在的神经病理生理机制却知之甚少。新出现的证据表明 持续慢性神经炎在神经艾滋病发病机制中的关键作用。当前的机械性调查 重点关注HIV-1有毒蛋白，如gp120和Tat在引发神经炎症中的作用。然而，鉴于目前的低点 ART后病毒载量，这些蛋白质的致病意义仍不确定。由于HIV患者需要 长期研究ART，我们认为测试替代可能性具有重要的临床意义：抗-ART 逆转录病毒疗法本身会引起神经炎性反应，即使它将HIV病毒载量控制在较低水平 抑制病毒诱导的免疫反应。这一假想疗法诱导的慢性 如果得到证实，神经炎症可能会对未来ART方案的设计产生深远影响。在这 研究中，我们将重点关注药物在当前ART中的潜在参与，特别是其主干 成分-核苷逆转录酶抑制剂(NRTI)。基于广泛的初步数据，我们 假设NRTI通过一种机制对慢性神经炎起关键作用 涉及WNT5a上调。具体地说，我们的假设需要NRTI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。慢性疾病的增加 炎症介质预计会导致神经艾滋病相关的神经元损伤。为了检验这一假设，我们 将表征NRTI诱导的中枢神经系统炎症(目标1)，阐明NRTI的机制- 诱导中枢神经系统炎症(目标2)，并确定NRTI诱导的中枢神经系统的病理生理作用 病理性疼痛发展中的神经炎症(目标3)。在概念上成功地完成了这些 创新研究将极大地促进我们对神经致病机制的理解 NRTIs/ART可能导致HIV患者的神经功能障碍。新的发现可能会导致进一步的 优化临床环境中的抗逆转录病毒治疗和开发抗逆转录病毒治疗佐剂以预防神经艾滋病，例如 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.