Pathways to HIV-Associated Neurocognitive Disorders: A Systems Biology Approach

描述(由申请人提供)：尽管广泛使用密集的抗逆转录病毒药物，但艾滋病毒相关神经认知障碍(HAND)的流行率仍然很高。多达50%的艾滋病毒感染者在他们的一生中会发展成某种程度的与艾滋病毒相关的神经认知障碍，范围从不会显著影响日常功能的轻微缺陷到衰弱的痴呆症。Hand很可能是慢性神经炎的结果，在很大程度上是由单核细胞渗透到大脑中介导的。使用包括可卡因和甲基苯丙胺在内的刺激性药物会加剧这种神经炎症，并随后加剧手部的严重程度。与HIV相关的痴呆相关的细胞级联事件已经被很好地描述，包括血液单核细胞表型的改变，以及脑组织内基因表达和蛋白质表达的变化。然而，绝大多数手都涉及潜伏的、通常是慢性的轻度神经认知缺陷，这些缺陷不会演变为痴呆症。尽管如此，与轻度手相关的细胞变化尚未被很好地描绘出来。在这项拟议的研究中，我们将应用创新的系统生物学方法来研究轻度手的发病机制。我们的研究重点是循环血单核细胞，因为这些细胞是这一发病机制的早期和关键组成部分。我们将使用由co-PI/PD开发的集成加权基因共表达网络分析(IWGCNA)，从单核细胞特异性基因表达微阵列、手部相关遗传标记和手部临床诊断中开发有意义的生物学途径。使用结构方程模型，然后我们将确定刺激剂的使用和病毒学生物标记物(例如病毒负载)如何修改这些途径。这一分析战略将首先在多中心艾滋病队列研究(MACS)的一大批艾滋病毒感染者身上实施。然后，我们将在国家神经艾滋病银行(NNAB)的另一个队列中验证我们的发现。为了完成这项雄心勃勃的研究，我们组建了一个合作团队，其中包括免疫学、系统生物学、神经艾滋病、神经心理学和遗传学的领导者。此外，由于我们将在很大程度上依赖现有的资源和数据，这项研究所需的金钱成本和患者负担非常低。这项研究的结果将有助于更好地了解HAND涉及的机制，提供潜在的HAND生物标志物，并确定药物预防和治疗的靶点。 公共卫生相关性：艾滋病毒相关神经认知障碍(HAND)的影响是巨大的，据估计，50%以上的艾滋病毒感染者在其一生中的某个时候会受到影响。了解手部的病因，特别是现在它已经转变为主要包括轻度和慢性损害，是至关重要的。这项研究试图确定与轻度手有关的生物学途径，并可能导致新的生物标记物和治疗靶点。

DESCRIPTION (provided by applicant): The prevalence of HIV-associated neurocognitive disorders (HAND) remains high despite widespread use of intensive antiretroviral medicines. Up to 50% of HIV-infected individuals will develop some degree of HIV-related neurocognitive impairment during their lifetimes, ranging from mild deficits that do not significantly impact day-to-day functioning to debilitating dementia. HAND is likely the result of chronic neuroinflammation, mediated in large part by the infiltration of monocytes into the brain. This neuroinflammation, and subsequently the severity of HAND, are enhanced by use of stimulant drugs, including cocaine and methamphetamine. The cellular cascade of events associated with HIV-associated dementia has been well-described, including alterations in the phenotype of blood monocytes, and changes in gene expression and protein expression within brain tissue. However, the vast majority of HAND involves insidious, often chronic mild neurocognitive deficits that do not evolve into dementia. Despite this, the cellular changes associated with mild HAND have not yet been well-delineated. In the proposed study, we will apply innovative systems biology approaches to the investigation of mild HAND pathogenesis. We focus our investigation on circulating blood monocytes, as these cells are an early and key component of this pathogenesis. We will use integrated weighted gene co-expression network analysis (IWGCNA), developed by the co-PI/PD, to develop meaningful biological pathways derived from monocyte-specific gene expression microarrays, HAND-associated genetic markers, and clinical diagnosis of HAND. Using structural equation modeling, we will then determine how stimulant use and virologic biomarkers (e.g. viral load) modify these pathways. This analytic strategy will first be implemented on a large cohort of HIV-infected individuals from the Multicenter AIDS Cohort Study (MACS). We will then validate our findings on a separate cohort from the National Neurological AIDS Bank (NNAB). To accomplish this ambitious study, we have assembled a collaborative team that includes leaders in immunology, systems biology, neuroAIDS, neuropsychology, and genetics. Further, because we will be relying largely on existing resources and data, the monetary cost and patient burden necessary for the study are extraordinarily low. The results of the study will lead to greater understanding of the mechanisms involved in HAND, provide potential biomarkers of HAND, and identify targets for pharmaceutical prophylactics and therapeutics. PUBLIC HEALTH RELEVANCE: The impact of HIV-associated neurocognitive disorders (HAND) is substantial, as it is estimated to affect upwards of 50% of HIV-infected individuals at some point during their lives. Understanding the etiology of HAND, especially now that it has shifted to include primarily mild and chronic impairments, is paramount. This study seeks to identify biological pathways involved in mild HAND, and could lead to novel biomarkers and therapeutic targets.