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: 9411197
• 负责人: Ling Cao
• 金额: $ 18.54万
• 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 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9411197
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adjuvant; Animal Model; Anti-Retroviral Agents; Antiviral Response; Area; Astrocytes; Astrocytosis; Behavior; Biological Models; Brain; Cells; Clinical; Cognitive; Cognitive deficits; Comorbidity; Corpus striatum structure; Data; Dendrites; Development; Disease; Drug abuse; Encephalopathies; Exhibits; 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; Neuraxis; Neurological outcome; Opioid; 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; Viral Load result; Virus; Virus Diseases; Zidovudine; behavioral impairment; frontal lobe; improved; innovation; mouse model; multiple sclerosis treatment; nervous system disorder; neuron loss; neurotoxicity; novel; novel strategies; 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.

总结 阿片类药物滥用显著增加HIV相关神经认知障碍的风险和严重程度 （手）。然而，对阿片类药物与艾滋病毒感染之间相互作用的理解还远远不够。 完成.在目前的研究中，我们建议探索调查之间的相互作用的潜力， 阿片类药物和HIV感染，通过组合两种不同但互补的啮齿动物模型：1）LP-BM 5模型， 其中鼠逆转录病毒分离物诱导严重免疫缺陷综合征（鼠AIDS，MAIDS）， 以及易感C57 BL/6（B6）小鼠的CNS脑病和认知缺陷;和2）HIV gp 120 转基因（HIV gp 120 tg）小鼠，其中HIV包膜蛋白gp 120是在 星形胶质细胞中胶质细胞酸性蛋白启动子。通过结合这两个模型，我们可以进一步研究 吗啡对HANDS样中枢神经系统损伤的作用 免疫缺陷状况。此外，I型干扰素（IFN）应答是关键的抗病毒先天免疫应答， IFNα和IFNβ通过其共同的受体IFNAR介导。从系统上讲，HIV-1可以 操纵宿主细胞I型IFN应答以建立持续感染。然而，类型的作用 I型干扰素在手仍然没有很好地界定，和参与的I型干扰素在手之间的阿片类药物使用者 仍不清楚我们建议进一步阐明I型干扰素在HANDs和吗啡共存中的作用 通过使用上述小鼠模型，使用并检查IFNβ的治疗潜力。我们 假设海马体中缺乏有效的I型IFN应答有助于 吗啡增强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，改善神经功能。这一核心假设将 通过两个具体目标进行测试。目标1.表征HIVgp 120 tg小鼠中的I型IFN应答（使用 野生型B6小鼠作为对照）进行LP-BM 5感染±吗啡处理。我们将研究 对艾滋病病毒敏感的区域，海马体和纹状体，与不太敏感的额叶相比。的 将评价感染、gp 120和吗啡对I型IFN应答的相互作用。目的 2.确定IFNβ在吗啡增强的神经病理学反应中的治疗潜力。通过 本研究将建立一个独特的小动物模型系统来研究HIV/HANDs和阿片类药物的作用 在手上。此外，我们正在朝着一种新的艾滋病毒感染的阿片类药物中HANDs的辅助治疗迈进。 用户.应该注意的是，IFNβ已成功地用作多种疾病的疾病修饰治疗， 硬化症因此，我们的研究结果可以相对快速地转化为临床应用。