Integration and Analysis of Diverse HIV-Associated Data in CHARTER

描述（申请人提供）：慢性HIV感染及其抗逆转录病毒治疗影响神经行为和社会心理功能，导致中枢神经系统的复杂特征。为了理解和分析这些，需要先进的统计方法和更大的集成数据集来分析多维和多学科数据之间的相互作用。此外，这些方法需要同时应用基线和纵向数据集来预测神经病理学、神经行为和神经心理学的风险和进展，以确定和开发新的预防和治疗干预措施。在这项R03申请中，我们建议对已经收集到的各种HIV相关数据进行二次分析，这些数据来自经过充分研究和充分表征的CHARTER （CNS HIV抗逆转录病毒治疗效应研究）队列，通过整合和组织这些数据来阐明它们之间复杂的相互作用（目标1），并开发预测定量模型（目标2），该模型可以识别因HIV及其相关疾病而面临更大不良神经行为和/或社会心理后果风险的受试者治疗方法。我们建议关注补体激活途径——一种涉及多种神经退行性和神经炎性疾病的特异性先天免疫反应机制，它也在外周血和中枢神经系统中产生关键的抗hiv反应。所有三种补体激活途径，即通过C1q的经典途径，通过HIV包膜蛋白的替代途径；MBL结合HIV gp120或gp41蛋白上的甘露糖残基激活的甘露糖结合凝集素介导途径；可能与艾滋病毒相互作用本提案的目的是最大限度地发挥以前从CHARTER队列收集的数据以及正在收集的数据的全部价值，以增强我们对hiv相关神经行为和神经社会心理后果的病因学和轨迹的理解，并帮助确定有效预防和治疗的新标记。我们建议整合和分析各种补体激活途径遗传学、炎症反应、病毒学、免疫学和神经心理学数据以及脑成像记录，以建立定量预测模型，以确定在入组时和纵向CHARTER队列中由于HIV感染和抗逆转录病毒治疗而导致不良神经认知结果风险更高的受试者。从这些研究中发展出来的二次分析和试点预测模型将在更多的基因中进一步测试，并与多中心艾滋病队列研究（MACS）等更大的队列合作。多学科数据的整合和分析将更好地为艾滋病毒相关神经认知障碍的可预测性和管理提供信息。

DESCRIPTION (provided by applicant): Chronic infection of HIV and its treatment with antiretrovirals have impacted the neurobehavioral and psychosocial functioning and resulted in complicated profiles of central nervous system. In order to understand and analyze these, advanced statistical approaches and larger integrated datasets are required for analyzing interactions among the multidimensional and multidisciplinary data. Furthermore, these approaches need to apply both the baseline and longitudinal data sets to predict the risk and progression of neuropathology, neurobehavioral and neuropsychological consequences for the identification and development of novel preventative and therapeutic interventions. In this R03 application we propose to do secondary analyses of already collected diverse HIV-associated data from well-studied and well-characterized CHARTER (CNS HIV Anti-Retroviral Therapy Effects Research) cohort by integrating and organizing these data for elucidating their complex interactions (aim 1) and develop predictive quantitative model (aim 2) that can identify subjects who are at greater risk for adverse neurobehavioral and/or psychosocial outcomes as a consequence of HIV and its treatments. We propose to focus on complement activation pathway - a specific innate immune response mechanism that is implicated in several neurodegenerative and neuroinflammatory diseases and it also mounts a critical anti-HIV response in peripheral blood and CNS. All three complement activation pathways, namely classical pathway through C1q, alternate pathway through HIV envelope proteins; and mannose binding lectin- mediated pathway activated by the MBL binding to the mannose residues on HIV gp120 or gp41 proteins; potentially interact with HIV. The aim of this proposal is to maximize the full value of previously collected data from CHARTER cohort as well as ongoing data collection to enhance our understanding of etiology and trajectories of HIV-associated neurobehavioral and neuropsychosocial consequences and to help identify novel markers for effective prevention and treatment. We propose to integrate and analyze diverse complement activation pathway genetics, inflammatory response, virologic and immunologic and neuropsychological data and brain imaging records to develop quantitative predictive models to identify subjects at greater risk for adverse neurocognitive outcomes as a consequence of HIV infection and antiretroviral treatment at the time of enrollment and in the longitudinal CHARTER cohort. The secondary analysis and pilot predictive modeling developed form these studies will be further tested for larger number of genes and in collaboration with larger cohorts such as Multicenter AIDS Cohort Study (MACS). Integration and analyses of multi-disciplinary data will better inform the predictability and management of HIV-associated neurocognitive disorders.