Systems Biology of Cognitive Decline in Older Adults with HIV Infection

描述(申请人提供)：本项目的目标是了解长期接受抗逆转录病毒治疗(ART)的老年HIV患者中脂代谢失调在HIV相关神经认知障碍(HAND)发展中的作用，以及这些过程如何受到肝功能障碍、慢性炎症和衰老的影响。长期抗逆转录病毒治疗与代谢异常和增加疾病风险有关，这些疾病通常与衰老有关，包括心血管、肝脏、肾脏、骨骼和神经疾病。长期接受抗逆转录病毒治疗的艾滋病毒患者中，30%-50%的人会受到轻度手部疾病的影响，50岁以上的艾滋病毒患者更常见。在初步研究中，我们进行了非靶向代谢物分析，在抑制ART的HIV患者的血浆中鉴定出126种代谢物改变，其中47%是脂类。血脂改变与肝脏和线粒体功能障碍的标志物相关，并代表不同于传统标志物的特定类别。根据使用归一化神经认知测试分数(T分数)的分析，一些属于特定类别的血脂变化与认知障碍有关，而另一些则主要与运动或执行功能缺陷有关。我们假设，由HIV或HIV/HCV感染引起的肝功能障碍、慢性炎症、一些抗逆转录病毒药物的肝毒性以及其他因素导致的脂代谢失调，促进了HIV感染的老年患者的白质异常和认知能力下降。衰老通过与衰老相关的脂代谢、线粒体功能、自噬和炎症反应的改变来改变这些过程。为了研究这一假设，我们将使用系统生物学方法来分析来自50岁及以上HIV患者的大规模临床、生物学、代谢组学和转录组学数据集，这些数据来自长期接受ART治疗的不同临床结果。将使用综合数据分析和有针对性的实验来通过计算建立相关网络和路径的模型。这些研究将创建一个新的概念框架，用于了解长期服用抗逆转录病毒药物的老年人的代谢途径，这可能为其他老龄化人群中认知和神经行为障碍的生物学提供重要见解，并开发新的治疗方法。

DESCRIPTION (provided by applicant): The goal of this project is to understand the role of dysregulated lipid metabolism in development of HIV-associated neurocognitive disorders (HAND) in older HIV patients on long-term antiretroviral therapy (ART), and how these processes are influenced by hepatic dysfunction, chronic inflammation, and aging. Long-term ART is associated with metabolic abnormalities and increased risk of diseases typically associated with aging including cardiovascular, liver, kidney, bone, and neurological disorders. Mild forms of HAND affect 30-50% of HIV patients on long-term ART, and are more frequent in HIV patients over age 50. In preliminary studies, we performed untargeted metabolite profiling and identified 126 metabolites altered in plasma of HIV patients on suppressive ART, of which 47% were lipids. Lipid alterations correlated with markers of hepatic and mitochondrial dysfunction, and represented specific classes distinct from traditional markers. Some altered lipids belonging to specific classes correlated with cognitive impairment, while others correlated primarily with deficits in motor or executive function, based on analyses using normalized neurocognitive test scores (T scores). We hypothesize that dysregulated lipid metabolism, a consequence of hepatic dysfunction induced by HIV or HIV/HCV infection, chronic inflammation, hepatotoxicity of some ART drugs, and other factors, promotes white matter abnormalities and cognitive decline in older adults with HIV infection. Aging modifies these processes through age-related alterations in lipid metabolism, mitochondrial function, autophagy, and inflammatory responses. To investigate this hypothesis, we will use systems biology approaches to analyze large-scale clinical, biological, metabolomics, and transcriptomics datasets from HIV patients age 50 and older on long-term ART with different clinical outcomes. Integrative data analysis and targeted experimentation will be used to computationally build models of relevant networks and pathways. These studies will create a new conceptual framework for understanding metabolic pathways driving HAND in older adults on long-term ART, which may provide important insights into the biology of cognitive and neurobehavioral disorders in other aging populations and developing new therapies.