Therapeutic potential of interferon (IFN)-beta for HIV-associated neurocognitive disorders (HAND) in opioid users

干扰素 (IFN)-β 对阿片类药物使用者的 HIV 相关神经认知障碍 (HAND) 的治疗潜力

• 批准号: 9535975
• 负责人: Ling Cao
• 金额: $ 16.1万
• 依托单位: UNIVERSITY OF NEW ENGLAND
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9535975
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adjuvant; Animal Model; Anti-Retroviral Agents; Antiviral Agents; Antiviral Response; Area; Astrocytes; Astrocytosis; Behavior; Biological Models; Brain; Cells; Clinical; Cognitive; Cognitive deficits; Comorbidity; Corpus striatum structure; Data; Dendrites; Development; Disease; Encephalopathies; Exhibits; Exposure to; Genes; Glial Fibrillary Acidic Protein; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Highly Active Antiretroviral Therapy; Hippocampus (Brain); Human; IFNAR1 gene; Immune; Immunologic Deficiency Syndromes; Individual; Infection; Interferon Type I; Interferon-alpha; Interferon-beta; Interferons; Investigation; Learning; Measures; Mediating; Memory; Modeling; Morphine; Murine Acquired Immunodeficiency Syndrome; Mus; Nervous System Trauma; Neuraxis; Neurological outcome; Opioid; Opioid user; Pathogenesis; Pathologic; Pathology; Patients; Performance; Pharmaceutical Preparations; Production; Proteins; Reporting; Risk; Rodent Model; Role; Severities; Severity of illness; Symptoms; Testing; Therapeutic; Time; Transgenic Organisms; Translating; Type I Epithelial Receptor Cell; Viral Load result; Virus; Virus Diseases; Zidovudine; behavioral impairment; chronic infection; frontal lobe; improved; innovation; mouse model; multiple sclerosis treatment; nervous system disorder; neurocognitive disorder; neuron loss; neurotoxicity; novel; novel strategies; opioid abuse; opioid use; prevent; promoter; receptor; response; subcutaneous

Summary Opioid drug abuse significantly increases the risk and severity of HIV-associated neurocognitive disorders (HANDs). However, the understanding of the interaction between opioids and HIV infection is far from complete. In the current study, we propose to explore the potential of investigating the interaction between opioids and HIV infection by combining two distinct, but complementary, rodent models: 1) the LP-BM5 model, in which a murine retroviral isolate induces a severe immunodeficiency syndrome (murine AIDS, MAIDS) as well as CNS encephalopathy and cognitive deficits in susceptible C57BL/6 (B6) mice; and 2) HIV gp120 transgenic (HIV gp120tg) mice, in which the HIV envelope protein gp120 is produced under the control of the glial fibrillary acidic protein promoter in astrocytes. By combining these two models, we can further examine the effects of morphine on HANDs-like CNS damage in the context of a live viral infection-induced immunodeficiency condition. Further, the type I interferon (IFN) response is a critical anti-viral innate immune mechanism and mediated by IFNα and IFNβ through their common receptor, IFNAR. Systemically, HIV-1 can manipulate the host cell type I IFN response in order to establish persistent infection. However, the role of type I IFNs in HANDs is still not well delineated, and the involvement of type I IFNs in HANDs amongst opioid users remains unclear. We propose to further delineate the roles of type I IFNs in co-existing HANDs and morphine use and examine the therapeutic potential of IFNβ through the use of the murine models mentioned above. We hypothesize that the lack of an efficient type I IFN response in the hippocampus contributes to morphine-potentiated infection-induced neurological disorders and that by supplying IFNβ, we can reduce morphine's detrimental effects and improve neurological outcomes. This central hypothesis will be tested through two Specific Aims. Aim 1. Characterize the type I IFN response in HIVgp120tg mice (using wild type B6 mice as controls) that are subjected to LP-BM5 infection ± morphine treatment. We will examine HIV-sensitive areas, the hippocampus and the striatum, in comparison to the less sensitive frontal lobe. The interactive effects between infection, gp120, and morphine on the type I IFN response will be evaluated. Aim 2. Determine the therapeutic potential of IFNβ in morphine-potentiated neuropathological responses. Through this study, we will establish a unique small animal model system to study HIV/HANDs and the effect of opioid on HANDs. Further, we are advancing towards a novel adjuvant treatment for HANDs in HIV-infected opioid users. It should be noted that IFNβ has been successfully used as a disease-modifying treatment for multiple sclerosis. As such, our results could relatively rapidly translate to clinical usage.

概括 阿片类药物滥用大大增加了与HIV相关神经认知疾病的风险和严重性 （手）。但是，对阿片类药物与艾滋病毒感染之间相互作用的理解远非 完全的。在当前的研究中，我们建议探索研究之间相互作用的潜力 通过组合两个不同但完整的啮齿动物模型：1）LP-BM5模型， 其中鼠逆转录病毒分离株诱导严重的免疫缺陷综合征（鼠类艾滋病，女仆） 以及易感C57BL/6（B6）小鼠的CNS脑病和认知缺陷； 2）HIV GP120 转基因（HIV GP120TG）小鼠，其中HIV包膜蛋白GP120在控制下产生 星形胶质细胞中的神经纤维原纤维酸性蛋白启动子。通过结合这两个模型，我们可以进一步研究 吗啡对现场病毒感染引起的类似手动中枢神经系统损伤的影响 免疫缺陷条件。此外，I型干扰素（IFN）反应是关键的抗病毒先天免疫 机理，由IFNα和IFNβ通过其公共受体IFNAR介导。从系统上讲，HIV-1可以 操纵宿主细胞I型IFN响应以建立持续感染。但是，类型的作用 我手中的IFN仍然没有很好地描述，并且I型IFN在阿片类药物用户中的参与 仍然不清楚。我们建议进一步描述I型IFN在共存的手和吗啡中的作用 通过使用上述鼠模型，使用并检查IFNβ的治疗潜力。我们 假设在海马中缺乏有效的I型IFN响应有助于 吗啡抑制感染引起的神经系统疾病，通过提供IFNβ，我们可以 减少吗啡的有害作用并改善神经系统效果。这个中心假设将 通过两个具体目标进行测试。 AIM 1。表征HIVGP120TG小鼠中I型IFN响应（使用 野生型B6小鼠作为对照），受到LP-BM5感染±吗啡治疗。我们将检查 与敏感的额叶相比，HIV敏感区域，海马和纹状体。 感染，GP120和吗啡之间对I型IFN响应的交互作用将得到评估。目的 2。确定IFNβ在吗啡训练的神经病理反应中的治疗潜力。通过 这项研究，我们将建立一个独特的小动物模型系统来研究艾滋病毒/手和Ooid的影响 在手上。此外，我们正在迈向一种新型的辅助治疗，用于感染HIV的阿片类药物 用户。应该注意的是，IFNβ已成功用作多种疾病改良治疗 硬化。因此，我们的结果可能会相对迅速地转化为临床用法。