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，我们建议研究海洛因滥用增加HIV感染者NCI风险的一种潜在机制。我们假设，海洛因成瘾者所经历的反复戒断综合症的生理压力可能引发有利于大脑病毒损伤的生理事件。具体来说，我们提出，禁欲诱导显著的下丘脑-垂体-肾上腺轴（HPA）和交感肾上腺髓质（SAM）激活，导致免疫变化，例如，淋巴细胞和单核细胞激活增加，并通过血脑屏障运输，以及诱导各种促炎分子，这些分子也可能有利于神经炎症。为了为这一假设建立“原理证明”，我们提出了一项R21初步研究，该研究将对俄罗斯50名海洛因戒毒者进行检查。医学、病毒学、神经内分泌、免疫和病毒学检测将在开始解毒后的3个时间点进行；7天后；在最初的解毒后大约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学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。这项研究将由俄罗斯圣彼得堡巴甫洛夫州立医科大学瓦尔德曼药理学研究所和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，并咨询了宾夕法尼亚大学的乔治·伍迪博士。在俄罗斯进行这项研究的时机有两个原因：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规定了症状管理，但没有阿片类药物替代（如美沙酮）。这使得在临床环境中研究戒断效应成为可能。如果成功建立这种合作并提供初步的原理证明，该研究可能会导致更成熟的研究，以建立抗逆转录病毒治疗和纳曲酮治疗，以减少解毒期间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.