A multi-systems study of HIV neuropathogenesis: genetics-neuropathology-behavior

描述（由申请人提供）： 尽管广泛使用联合抗逆转录病毒治疗（cART），但HIV相关神经认知障碍（HAND）的患病率仍接近50%。HAND是一种基于神经认知障碍的临床诊断，其严重程度从轻度神经认知缺陷到使人衰弱的痴呆。HAND是由宿主免疫激活引起的慢性神经炎症状态的结果;然而，涉及的关键病理生理途径仍不清楚。近年来，已发现少数宿主遗传易感性位点增加HAND的风险或影响其病程，表明其基因产物参与的生理途径的扰动改变了HAND的发病机制。然而，所有关于手相关遗传易感性基因座的研究都仅依赖于临床结果;对这些遗传变异导致的病理生理变化一无所知。 确定遗传易感性位点影响HAND的病理生理机制的一种创新方法是检查它们对神经病理中间表型或NIP的影响。在其最基本的水平上，HAND被认为是一系列生理事件的最终结果，这些生理事件始于由遗传因素修饰的HIV诱导的细胞变化。在本研究的背景下，我们认为可量化的神经病理学变化发生在HAND发病机制的因果链的开始附近，作为HAND行为障碍特征所必需的NIP。存在许多与HAND相关的候选NIP，包括突触树突简化、巨噬细胞浸润、小胶质细胞和星形胶质细胞活化以及β-淀粉样蛋白沉积。通过检查遗传易感性基因座与来自临床充分表征的队列的脑组织中的NIP之间的关系，将有可能确定1）哪些遗传变异与HAND生物学相关，2）它们对神经行为表型发挥作用的病理生理学机制，以及3）NIP作为HAND潜在致病因素的相对重要性。 这项研究与NIH的使命高度相关，以阐明导致HAND的生理机制。为了实现我们的目标，我们将使用免疫组织化学和高通量定量程序来表征多个脑区域的NIP。我们的目标是确定基因型和重要的辅助因子（例如，年龄、药物使用、cART使用）修改这些NIP。我们的第二个目标是确定遗传易感基因座、NIP和神经认知障碍之间的线性因果关系。为此，我们将使用网络边缘定位来确定基因型和NIP之间的因果关系。这将与结构方程建模相结合，从而允许创建一个全面的HAND通路模型，包括基因型，NIP，神经认知功能和重要的辅助因子。 公共卫生相关性： HIV相关的神经认知障碍（HAND）的影响是巨大的，影响了50%以上的HIV感染者;因此，阐明这种疾病的神经发病机制并确定药物靶点将改善美国数万人的生活质量。近年来，已经确定了少量的遗传易感性基因座，增加了HAND的风险，这表明其基因产物参与的生理途径的扰动改变了HAND的发病机制;然而，这些遗传变异导致的病理生理变化尚不清楚。阐明这种关系将有助于阐明参与HAND神经发病机制的分子和生理途径，这将导致识别潜在的药物靶点。

DESCRIPTION (provided by applicant): The prevalence of HIV-associated neurocognitive disorders (HAND) is near 50% despite the widespread use of combined antiretroviral therapy (cART). HAND is a clinical diagnosis based on neurocognitive impairments ranging in severity from mild neurocognitive deficits to a debilitating dementia. HAND is the result of a chronic neuroinflammatory state fueled by host immune activation; however, the key pathophysiological pathways involved remain unclear. In recent years, a small number of host genetic susceptibility loci have been identified that increase risk for HAND or influence its course, suggesting that perturbation of the physiological pathways their gene products are involved in modifies HAND pathogenesis. However, all studies of HAND-related genetic susceptibility loci have relied solely on clinical outcomes; nothing is known of what pathophysiological changes these genetic variants cause. An innovative approach for determining the pathophysiological mechanisms through which genetic susceptibility loci influence HAND is to examine their influence on neuropathological intermediate phenotypes, or NIPs. At its most basic level, HAND is believed to be the end result of a sequence of physiological events that commences with HIV-induced cellular changes that are modified by genetic factors. In the context of the present study, we deem quantifiable neuropathological changes that occur proximal to the beginning of this causal chain of HAND pathogenesis as the NIPs necessary for the behavioral impairments characteristic of HAND. There exist a number of candidate NIPs that are associated with HAND, including synaptodendritic simplification; macrophage infiltration; microglial and astrocyte activation, and beta-amyloid deposition. Through examining the relationship between genetic susceptibility loci and NIPs in brain tissue derived from a clinically well-characterized cohort, it will be possible t determine 1) which genetic variants are biologically relevant to HAND, 2) the pathophysiological mechanisms through which they exert their effect on the neurobehavioral phenotypes, and 3) the relative importance of NIPs as underlying causative factors of HAND. This study is highly relevant to the mission of NIH to elucidate the physiological mechanisms leading to HAND. To accomplish our aims, we will use immunohistochemistry and high throughput quantification procedures to characterize NIPs across multiple brain regions. Our aim is to determine the extent to which genotype and important co-factors (e.g., age, substance use, cART use) modify these NIPs. Our second aim will determine the linear causative relationship between genetic susceptibility loci, NIPs, and neurocognitive impairment. Towards this end we will use Network Edge Orienting to determine the causative relationship between genotype and NIPs. This will be integrated with structural equation modeling, thus allowing creation of a comprehensive pathway model of HAND that includes genotype, NIPs, neurocognitive functioning, and important co-factors. PUBLIC HEALTH RELEVANCE: The impact of HIV-associated neurocognitive disorders (HAND) is substantial, affecting upwards of 50% of HIV-infected individuals; therefore, elucidating the neuropathogenesis of this disorder and identifying pharmaceutical targets will improve quality of life for tens of thousands within th United States alone. In recent years, a small number of genetic susceptibility loci have been identified that increase risk for HAND, suggesting that perturbation of the physiological pathways their gene products are involved in modifies HAND pathogenesis; however, nothing is known of what pathophysiological changes these genetic variants cause. Delineating this relationship will help to clarify the molecular and physiological pathways involved in HAND neuropathogenesis, and this will lead to identification of potential pharmaceutical targets.