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

描述（由申请人提供）：尽管广泛使用强化抗逆转录病毒药物，hiv相关神经认知障碍（HAND）的患病率仍然很高。多达50%的艾滋病毒感染者在其一生中会出现某种程度的与艾滋病毒相关的神经认知障碍，从不会显著影响日常功能的轻度缺陷到使人衰弱的痴呆症。HAND可能是慢性神经炎症的结果，在很大程度上是由单核细胞浸润到大脑所介导的。使用兴奋剂（包括可卡因和甲基苯丙胺）会增强这种神经炎症以及随后的HAND的严重程度。与hiv相关的痴呆相关的细胞级联事件已经得到了很好的描述，包括血液单核细胞表型的改变，以及脑组织中基因表达和蛋白质表达的变化。然而，绝大多数HAND涉及潜伏的，通常是慢性轻度神经认知缺陷，不会演变成痴呆。尽管如此，与轻度HAND相关的细胞变化尚未得到很好的描述。在拟议的研究中，我们将应用创新的系统生物学方法来研究轻度HAND发病机制。我们的研究重点是循环血液单核细胞，因为这些细胞是这种发病机制的早期和关键组成部分。我们将使用由co-PI/PD开发的综合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、HAND相关遗传标记和HAND的临床诊断中开发有意义的生物学途径。使用结构方程模型，我们将确定兴奋剂的使用和病毒学生物标志物（如病毒载量）如何改变这些途径。这一分析策略将首先在多中心艾滋病队列研究（MACS）的一个大型艾滋病毒感染者队列中实施。然后，我们将在国家神经系统艾滋病银行（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，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，由于我们将主要依靠现有的资源和数据，因此研究所需的金钱成本和患者负担非常低。该研究结果将有助于进一步了解HAND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。

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.