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

摘要 阿片类药物滥用显著增加艾滋病毒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的相互作用的了解还远远不够 完成。在目前的研究中，我们建议探索研究相互作用的可能性 阿片类药物和艾滋病毒感染通过结合两个不同但互补的啮齿动物模型：1)LP-BM5模型， 在这种情况下，小鼠逆转录病毒分离株会导致严重的免疫缺陷综合征(小鼠艾滋病，女佣) 以及易感C57BL/6(B6)小鼠的中枢神经系统脑病和认知障碍；以及2)HIV gp120 转基因(HIV Gp120tg)小鼠，其中HIV包膜蛋白gp120是在 星形胶质细胞中的胶质纤维酸性蛋白启动子。通过将这两个模型结合起来，我们可以进一步研究 在活体病毒感染的背景下吗啡对手状中枢神经系统损伤的影响 免疫缺陷状态。此外，I型干扰素(IFN)反应是一种关键的抗病毒先天免疫。 干扰素α和干扰素β通过其共同的受体干扰素受体介导。从系统上讲，HIV-1可以 操纵宿主细胞的I型干扰素反应，以建立持续感染。然而，类型的作用 手中的I型IFN仍然没有很好地描述，以及阿片类药物使用者手中I型IFN的参与情况 目前仍不清楚。我们建议进一步描述I型干扰素在共存的手和吗啡中的作用。 通过使用上述小鼠模型，使用并检测干扰素β的治疗潜力。我们 假设海马区缺乏有效的I型干扰素反应 通过提供干扰素β，我们可以 减少吗啡的有害影响，改善神经学结果。这一中心假说将 通过两个具体的目标进行测试。目的1.研究HIVgp120tg小鼠的I型干扰素应答(使用 野生型B6小鼠作为对照)，接受Lp-BM5感染+吗啡治疗。我们将研究 与对艾滋病毒不敏感的额叶相比，对艾滋病毒敏感的区域，即海马体和纹状体。这个 将评估感染、gp120和吗啡对I型干扰素反应的交互作用。目标 2.确定干扰素β对吗啡增强的神经病理反应的治疗作用。穿过 本研究中，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 在手中。此外，我们正在向艾滋病毒感染阿片类药物手的一种新的辅助治疗迈进 用户。应该指出的是，干扰素β已经成功地用于治疗多发性硬化症 硬化症。因此，我们的结果可以相对较快地转化为临床应用。

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.