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。药物滥用是持续性NCI的危险因素之一。在这项研究中，我们建议检查一个潜在的机制，海洛因滥用增加艾滋病毒感染者的NCI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引发有利于病毒损伤大脑的生理事件。具体来说，我们认为禁欲诱导下丘脑-垂体-肾上腺轴（HPA）和交感肾上腺髓质（SAM）激活，导致免疫学变化，例如，增加淋巴细胞和单核细胞活化和穿过血脑屏障的运输，以及诱导也可能有利于神经炎症的各种促炎分子。为了建立一个“原则证明”这一假设，我们提出了一个R21初步研究，这将检查50个海洛因脱毒个人在俄罗斯。将在3个时间点进行医学、病毒学、神经内分泌、免疫和病毒学检测-开始脱毒后立即; 7天后;以及初始脱毒后约4周。我们将把HPA和SAM激活的变化与促炎生物标志物的通量和病毒控制的改变联系起来，并将这些与神经认知障碍的波动联系起来。这项研究将通过俄罗斯圣彼得堡巴甫洛夫州立医科大学Valdman药理学研究所的研究人员与加州大学圣地亚哥分校HIV神经行为研究项目的研究人员合作进行，并与宾夕法尼亚大学的乔治伍迪博士进行磋商。在俄罗斯进行这项研究是合适的，原因有两个：1）海洛因使用是东欧主要的艾滋病毒风险因素，因此这项工作具有高度相关性; 2）俄罗斯的海洛因戒毒实践要求进行症状管理，但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变得可行。如果成功地建立这种合作并提供初步的原则证明，这项研究可能会导致更成熟的研究，建立抗逆转录病毒治疗和纳洛酮治疗，以减少戒毒期间神经毒性事件的可能性的影响。

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.