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

尽管广泛使用，但艾滋病毒相关神经认知障碍(HAND)的患病率仍然很高 密集的抗逆转录病毒药物。多达50%的艾滋病毒感染者会患上不同程度的 艾滋病毒相关的神经认知障碍，从轻微的缺陷到不 对衰弱的痴呆症患者的日常功能有显著影响。手可能是慢性疾病的结果 神经炎症，在很大程度上是由单核细胞渗入大脑所介导的。这 神经炎症，以及随后手部的严重程度，通过使用兴奋剂而增加， 包括可卡因和冰毒。与HIV相关的细胞级联事件 痴呆症已经得到了很好的描述，包括单核细胞表型的改变，以及 脑组织内基因表达和蛋白表达的变化。然而，绝大多数人 Hand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 建议的研究，我们将应用创新的系统生物学方法来研究轻度手 发病机制。我们的研究重点是循环血单核细胞，因为这些细胞是一种早期和 这是这一发病机制的关键组成部分。我们将使用集成的加权基因共表达网络 分析(IWGCNA)，由共同PI/PD开发，以开发来自以下方面的有意义的生物途径 单核细胞特异性基因表达微阵列、手性遗传标记和临床诊断 手中的。使用结构方程模型，然后我们将确定如何使用兴奋剂和病毒学 生物标记物(如病毒载量)修饰这些途径。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。到时候我们会的 在国家神经艾滋病库(NNAB)的一个单独的队列中验证我们的发现。至 为了完成这项雄心勃勃的研究，我们组建了一个协作团队，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。更进一步，因为我们将 在很大程度上依赖于现有资源和数据， 学习水平低得出奇。这项研究的结果将有助于更好地了解 涉及手部的机制，提供潜在的手部生物标记物，并确定目标 药物预防和治疗。

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 be 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.