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

基本信息

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
项目类别：
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

项目摘要

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显着增加艾滋病毒相关神经认知障碍的风险和严重程度（HANDs）然而，人们对阿片类药物和艾滋病毒感染之间相互作用的了解还很遥远。在当前的研究中，我们建议探索研究之间相互作用的潜力。通过结合两种不同但互补的啮齿动物模型来研究阿片类药物和 HIV 感染：1) LP-BM5 模型，其中鼠逆转录病毒分离株诱发严重的免疫缺陷综合症（鼠艾滋病，MAIDS）以及易感 C57BL/6 (B6) 小鼠的中枢神经系统脑病和认知缺陷；以及 2) HIV gp120 转基因（HIV gp120tg）小鼠，其中 HIV 包膜蛋白 gp120 是在通过结合这两个模型，我们可以进一步检查星形胶质细胞中的胶质纤维酸性蛋白启动子。吗啡对活病毒感染引起的 HANDs 样中枢神经系统损伤的影响此外，I 型干扰素 (IFN) 反应是一种重要的抗病毒先天免疫。 HIV-1 可以通过 IFNα 和 IFNβ 的共同受体 IFNAR 介导。操纵宿主细胞I型IFN反应以建立持续感染的作用。 HAND 中的 I 型 IFN 仍不清楚，并且阿片类药物使用者中 HAND 中 I 型 IFN 的参与情况目前仍不清楚。我们建议进一步描述 I 型 IFN 在共存的 HAND 和吗啡中的作用。我们通过使用上述小鼠模型来使用和检查 IFNβ 的治疗潜力。证实海马体缺乏有效的 I 型干扰素反应导致吗啡增强的感染诱发的神经系统疾病，通过提供 IFNβ，我们可以减少吗啡的痛苦作用并改善神经系统结果。通过两个具体目标进行测试目标 1. 表征 HIVgp120tg 小鼠中的 I 型 IFN 反应（使用）。野生型 B6 小鼠作为对照）接受 LP-BM5 感染±吗啡治疗。与不太敏感的额叶相比，海马体和纹状体对艾滋病毒敏感。将评估感染、gp120 和吗啡对 I 型 IFN 反应之间的相互作用。 2. 确定 IFNβ 在吗啡增强的神经病理反应中的治疗潜力。在这项研究中，我们将建立一个独特的小动物模型系统来研究 HIV/HAND 和阿片类药物的作用此外，我们正在开发一种针对 HIV 感染的阿片类药物的新型辅助治疗方法。值得注意的是，IFNβ 已成功用于多种疾病的缓解治疗。因此，我们的结果可以相对快速地转化为临床应用。