Heroin abstinence induced HPA & SAM dysregulation disrupts HIV virologic control

描述(由申请人提供)：神经认知障碍(NCI)仍然是HIV感染的常见并发症。药物滥用是持续NCI的危险因素之一。在这项研究中，我们建议研究一种潜在的机制，即海洛因滥用会增加艾滋病毒感染者发生非传染性脑感染的风险。我们推测，海洛因成瘾者经历的反复戒断综合征的生理应激可能会触发有利于脑部病毒性损伤的生理事件。具体地说，我们认为，禁欲诱导了显著的下丘脑-垂体-肾上腺轴(HPA)和交感肾上腺髓质(SAM)的激活，导致免疫学变化，例如，淋巴细胞和单核细胞的激活和跨血脑屏障的运输增加，以及各种促炎分子的诱导，这些分子也可能有利于神经炎症。为了建立这一假设的“原则证据”，我们提出了一项R21初步研究，该研究将检查俄罗斯的50名海洛因戒毒者。医学、病毒学、神经内分泌、免疫和病毒学检测将在3个时间点进行--即开始戒毒时、7天后和最初戒毒后约4周。我们将HPA和SAM激活的变化与促炎生物标志物的通量和病毒学控制的变化联系起来，并将这些与神经认知损害的波动联系起来。这项研究将由俄罗斯圣彼得堡巴甫洛夫州立医科大学瓦尔德曼药理研究所、加州大学圣地亚哥分校艾滋病毒神经行为研究项目的研究人员合作进行，宾夕法尼亚大学的乔治·伍迪博士将提供咨询。在俄罗斯进行这项研究是合适的，原因有两个：1)海洛因使用是东欧艾滋病毒的主要风险因素，因此这项工作具有很高的相关性；2)俄罗斯的海洛因戒毒实践要求对症治疗，而不是阿片类药物替代(例如美沙酮)。这使得在临床环境中研究戒断效应是可行的。如果成功地建立了这一合作并提供了初步的原则证据，这项研究可能会导致对实施抗逆转录病毒治疗和纳曲酮治疗的效果进行更成熟的研究，以减少戒毒期间发生神经毒性事件的可能性。

DESCRIPTION (provided by applicant): Neurocognitive impairment (NCI) continues to be a frequent complication of HIV infection. Drug abuse represents one of the risk factors for persisting NCI. In this study we propose to examine one potential mechanism whereby heroin abuse increases risk for NCI in HIV infected persons. We hypothesize that the physiological stress of repeated abstinence syndromes that heroin addicts experience may trigger physiologic events that favor viral injury of the brain. Specifically, we propose that abstinence induces significant hypothalamic-pituitary-adrenal axis (HPA) and sympathoadrenal medullary (SAM) activation leading to immunological changes, e.g., increased lymphocyte and monocyte activation and trafficking across the blood-brain-barrier, as well as induction of various proinflammatory molecules that may also favor neuroinflammation. To establish a "proof of principle" for this hypothesis we propose a R21 preliminary study, which will examine 50 heroin-detoxifying individuals in Russia. Medical, virologic, neuroendocrine, immune, and virologic assays will be conducted at 3 time points - immediately upon beginning detoxification; 7 days later; and approximately 4 weeks after initial detoxification. We shall relate changes in HPA and SAM activation to fluxes in proinflammatory biomarkers and alterations in virologic control, and link these to fluctuations in neurocognitive impairment. The research will be conducted via a collaboration between investigators at the Valdman Institute of Pharmacology, Pavlov State Medical University, Saint Petersburg, Russia, the HIV Neurobehavioral Research Program at the University of California, San Diego, with consultation from Dr. George Woody at the University of Pennsylvania. Performing this research in Russia is opportune for two reasons: 1) heroin use is the major HIV risk factor in Eastern Europe, hence this work has high relevance; 2) heroin detox practice in Russia dictates symptomatic management, but not opioid substitution (e.g., methadone). This makes it feasible to study withdrawal effects in a clinical setting. If successful in establishing this collaboration and providing initial proof of principle, this study ay lead to more mature research on effects of instituting antiretroviral treatment and naltrexone therapy to reduce likelihood of neurotoxic events during detoxification.