Inflammation associated with HIV infection: role of receptor cross-talk

与 HIV 感染相关的炎症：受体串扰的作用

• 批准号: 10190879
• 负责人: Yuri Persidsky
• 金额: $ 65.71万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190879
• 关键词: Ache; Acquired Immunodeficiency Syndrome; Acute; Address; Agonist; Analgesics; Animals; Attenuated; Axonal Neuropathy; Bilateral; Blood - brain barrier anatomy; Brain; Bromides; CCL2 gene; CCL3 gene; CCL4 gene; CCR1 gene; CCR5 gene; Cells; Chemotaxis; Chronic; Development; Disease; Enkephalins; Epidemic; Event; Exposure to; Failure; Fiber; Foundations; Generations; Genetic; HIV; HIV Envelope Protein gp120; HIV Infections; Headache; Highly Active Antiretroviral Therapy; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Intravenous; Intravenous Drug Abuse; Ligands; Link; Morbidity - disease rate; Morphine; Mouse Strains; Mus; Neurologic; Neuropathy; Opioid; Opioid Analgesics; Opioid Antagonist; Opioid Receptor; Opioid abuser; Organ; Pain; Pain management; Pathologic; Patients; Phosphorylation; Play; Population; Process; Production; Proteins; Receptor Activation; Receptor Cross-Talk; Recurrent pain; Reporting; Role; Signal Pathway; Stimulus; Syndrome; Testing; Transgenic Mice; antiretroviral therapy; base; chemokine; chemokine receptor; chronic pain; clinically significant; cytokine; desensitization; drug abuser; humanized mouse; in vivo; morphine administration; mortality; mouse model; mu opioid receptors; neuroinflammation; novel; opiate tolerance; opioid abuse; pain sensitivity; painful neuropathy; release of sequestered calcium ion into cytoplasm; response

Abstract: Opiate drug abuse is a critical contributor to the global AIDS epidemic, and over a third of HIV infections in the U.S. can be linked to intravenous drug abuse. Recent estimates suggest that almost 20% of intravenous drug abusers are infected with HIV. HIV-associated neuropathy remains a clinically significant issue for patients infected with HIV, even in the current era of anti-retroviral therapy. In addition, HIV-infected opiate abusers demonstrate a more severe neuropathy than non-opiate abusers, and the basis for the greater neuropathy remains uncertain. In this application, we propose that HIV infection in the brain results in an inflammatory response, which promotes the production of inflammatory chemokines, leading to the activation of the respective chemokine receptors, resulting in the cross-desensitization of opioid receptors. The consequence of this set of events is an elevated sensitivity to pain stimuli. We propose to test these processes using mouse models to evaluate the influence of HIV gp120 in the induction of neuroinflammation, including the associated neuropathic pain. Our proposed studies will also attempt to address the ability of morphine to attenuate the development of this pain response. We also propose to confirm these studies through the analysis of an authentic HIV infection using a humanized mouse model. We believe the results from these studies will greatly enhance our understanding of the mechanisms which contribute to the development of neuroinflammation in HIV-infected subjects, including those who are opiate abusers.

摘要： 鸦片类药物滥用是全球艾滋病流行的关键因素，超过三分之一的艾滋病毒 在美国，感染可能与静脉注射药物滥用有关。最近的估计表明， 近20%的静脉注射吸毒者感染了艾滋病毒。HIV相关神经病 对于感染艾滋病毒的患者来说，仍然是一个具有临床意义的问题，即使在当前的 抗逆转录病毒疗法。此外，感染艾滋病毒的阿片类药物滥用者表现出更严重的 与非阿片类药物滥用者相比，神经病变更严重的基础仍然是 不确定。在这个应用中，我们认为大脑中的艾滋病毒感染会导致 炎症反应，促进炎性趋化因子的产生，导致 激活各自的趋化因子受体，导致交叉脱敏 阿片受体。这一系列事件的结果是对疼痛刺激的敏感度提高。 我们建议使用小鼠模型来测试这些过程，以评估艾滋病毒的影响 Gp120可诱导神经炎症，包括相关的神经病理性疼痛。我们的 拟议中的研究还将试图解决吗啡是否能够减弱 这种疼痛反应的发展。我们亦建议透过 使用人源化小鼠模型分析一例真实的艾滋病毒感染。我们相信结果 这些研究将极大地提高我们对 与HIV感染者的神经炎症的发展有关，包括那些 鸦片滥用者。