HIV-induced neuroinflammation associated with opiod abuse and tobacco smoke

 描述（由申请人提供）：阿片类药物滥用是全球艾滋病流行的关键因素，美国超过三分之一的艾滋病毒感染与静脉注射药物滥用有关。最近的估计表明，几乎20%的静脉注射药物滥用者感染了艾滋病毒。吸烟在艾滋病毒感染者中很普遍，在静脉注射吸毒者中也很常见。重要的是，吸烟与许多非艾滋病疾病密切相关，包括慢性阻塞性肺病（COPD），这种慢性炎症性疾病可能有助于与HIV感染相关的神经炎症的发展。然而，人们对烟草烟雾和慢性阿片类药物给药对炎症反应发展的联合作用知之甚少，甚至更不了解这些临床相关药物对HIV感染后神经变性发展的影响。我们描述的初步数据表明，烟草和阿片类药物联合给药后，炎症反应在定量和定性上都是不同的。我们建议使用人源化小鼠进行实验，以检查慢性烟草烟雾暴露与慢性吗啡给药对HIV诱导的神经炎症的发展的综合影响。我们发表的和初步的数据表明，血脑屏障是阿片类药物和/或烟草的作用的目标，以及单核细胞和巨噬细胞的炎症活性。我们建议研究这些药物治疗对这些细胞群的联合作用的机制基础。我们相信，这些研究将提供关于吗啡和烟草烟雾在临床相关免疫学背景下对HIV相关神经变性影响的高度新颖的信息。

 DESCRIPTION (provided by applicant): 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. Tobacco smoking is prevalent in HIV-infected patients, and is very common among intravenous drug abusers. Importantly, smoking is strongly associated with a number of non-AIDS conditions, including chronic obstructive lung disease (COPD), and this chronic inflammatory disease may contribute to the development of neuroinflammation associated with HIV infection. However, there is very little known about the combined effects of tobacco smoke and chronic opioid administration on the development of inflammatory responses, and even less known about the effects of these clinically relevant drugs on the development of neurodegeneration following HIV infection. We describe preliminary data which shows that the inflammatory response is both quantitatively and qualitatively distinct following the combination of tobacco and opiate administration. We propose to conduct experiments using humanized mice to examine the combined effects of chronic tobacco smoke exposure with and without chronic administration of morphine on the development of HIV-induced neuroinflammation. Our published and preliminary data show that the blood-brain barrier is a target for the effects of opiates and/or tobacco, as well as the inflammatory activity of monocytes and macrophages. We propose to investigate the mechanistic basis for the combined effects of these drug treatments on these cell populations. We believe the proposed studies will provide highly novel information about the effects of morphine and tobacco smoke on HIV-associated neurodegeneration in a clinically relevant immunological context.