Host Glycomic Modulation of HIV-associated Neuro-inflammation During Viral Suppression

病毒抑制过程中宿主糖组对 HIV 相关神经炎症的调节

• 批准号: 10373025
• 负责人: Mohamed Abdel Mohsen
• 金额: $ 84.7万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373025
• 关键词: Acute; Affect; Animal Model; Anti-Inflammatory Agents; Antibodies; Antiinflammatory Effect; Attenuated; Behavior; Binding; Binding Proteins; Brain; Carbohydrates; Cells; Cerebrospinal Fluid; Chronic; Clinical; Cognition Disorders; Cognitive; Data; Development; Discipline; Disease; Engineering; Enzymes; Fc Receptor; Flow Cytometry; Genes; Glycoproteins; HIV; HIV Infections; HIV antiretroviral; HIV-associated neurocognitive disorder; Immune response; Immunity; Immunoglobulin G; Immunohistochemistry; Impaired cognition; Impairment; Individual; Inflammation; Inflammation Mediators; Inflammatory; Investigation; Lasers; Lectin; Leukocytes; Link; Literature; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Neuraminidase; Neuraxis; Neurocognitive Deficit; Neurologic; Organ; Pathogenesis; Pattern; Physiological Processes; Plasma; Play; Polysaccharides; Population; Prevalence; Process; Recovery; Role; Sialic Acids; Signal Transduction; Structure; Surface; TLR4 gene; Testing; Viral; Virus; Work; antiretroviral therapy; base; biological systems; brain tissue; cognitive development; comorbidity; exosome; humanized mouse; immune activation; inflammatory marker; inhibitor; macrophage; migration; monocyte; mortality; mouse model; nanoparticle; neurocognitive disorder; neuroinflammation; novel; novel therapeutics; prevent; sialic acid binding Ig-like lectin; sialylation; targeted treatment

PROJECT SUMMARY: Despite the widespread use of antiretroviral therapy (ART), the prevalence of neuro- inflammation remains high and is believed to involve >40% of HIV+ individuals. This inflammatory state likely causes cognitive dysfunction that impacts everyday functioning and increases morbidity and mortality among ART-suppressed HIV-infected individuals. However, the physiological processes underlying this neuro- inflammation remain poorly understood. This proposal builds on our ongoing investigation on whether glycomic alterations in circulating glycoproteins and exosomes play a role in the pathogenesis of HIV-associated neuro- inflammation and cognitive disorders. Our preliminary data demonstrate that higher levels of the pro- inflammatory hypo-sialylated glycans in plasma, plasma exosomes, and cerebrospinal fluid (CSF) strongly correlate with worse neurological impairment in HIV+ ART-suppressed individuals. However, whether glycomic alterations drive neuro-inflammation during HIV infection remains unknown. In this project we will test the central hypothesis that host glycomic dysregulation, in particular hypo-sialyation of circulating glycoproteins and exosomes, contributes to neuroinflammation and the pathogenesis of HIV-associated co- morbidities affecting the central nervous system (CNS). In Aim 1, we will identify the mechanism of the neuro-inflammatory effects of hypo-sialylated glycans during ART-suppressed HIV infection. We will use hyper-sialylated and hypo-sialylated glycoproteins and exosomes isolated from the plasma of HIV+ ART+ individuals with neurological impairments, in an ex-vivo model of monocyte activation/inflammation and migration, in the presence or absence of glycan signaling inhibitors. In Aim 2, we will test the hypothesis that manipulating the levels of circulating sialic acid impacts neuro- inflammation and cognitive behavior in a mouse model of HIV-associated neurological impairment. We will use the EcoHIV mouse model (using chimeric HIV capable of infecting mice) that was recently used as a successful model of HIV pathogenesis and neurological impairment. Using acutely and chronically EcoHIV-infected mice (with and without ART), that receive either a combination of sialic acid nanoparticles and sialidase inhibitors or nude nanoparticles as controls, we will evaluate: (1) levels of cognitive impairment; (2) brain markers of inflammation/immune activation [gene array and immunohistochemistry]; (3) EcoHIV expression in brain tissues [qPCR]; and (4) sialylation of brain tissues and brain-derived exosomes [lectin array and flow cytometry]. We will take advantage of recent advances in the emerging field of glycomics and an animal model of HIV-associated neurological impairment, to clarify the inter-related mechanisms between neuro-inflammation, cognitive dysfunction, and host immunity. Our work aims to create a new paradigm for discovering novel glycan- based interactions that can be targeted to prevent neuro-inflammation that persists in individuals living with HIV despite viral suppression.

项目摘要：尽管广泛使用抗逆转录病毒疗法（ART），但神经的流行率 炎症仍然很高，据信涉及40％的HIV+个体。这种炎症状态可能 引起认知功能障碍，会影响日常功能并增加发病率和死亡率 被艺术抑制的艾滋病毒感染者。但是，该神经的生理过程 炎症仍然很少理解。这项建议是基于我们正在进行的有关糖果实的调查 循环糖蛋白和外泌体的改变在与HIV相关神经的发病机理中起作用 炎症和认知障碍。我们的初步数据表明，较高水平的亲 血浆，血浆外泌体和脑脊液（CSF）中的炎症性低糖化聚糖强烈 与艾滋病毒+艺术抑制的个体中的神经障碍较差有关。但是，是否糖 促进HIV感染期间神经炎症的改变仍然未知。在这个项目中，我们将测试中央 假设宿主糖化失调，特别是循环糖蛋白的低归化 和外泌体有助于神经炎症和HIV相关共同的发病机理 影响中枢神经系统（CNS）的病态。 在AIM 1中，我们将确定低溶解聚糖的神经炎症作用的机制 在被毒Art抑制的艾滋病毒感染期间。我们将使用超磷酸化和低溶解的糖蛋白和 从HIV+ ART+患有神经系统障碍的个体的血浆中分离出的外泌体，在前体模型中 在存在或不存在聚糖信号抑制剂的情况下，单核细胞激活/炎症和迁移。在 AIM 2，我们将测试以下假设：操纵循环唾液酸的水平会影响神经 - 与HIV相关神经系统障碍的小鼠模型中的炎症和认知行为。我们将使用 最近用作成功的EcoHIV小鼠模型（使用能够感染小鼠的嵌合HIV感染小鼠） HIV发病机理和神经系统障碍的模型。使用急性和慢性生态感染的小鼠 （有和没有艺术），可以接受唾液酸纳米颗粒和唾液酸酶抑制剂的组合或 裸纳米颗粒作为对照，我们将评估：（1）认知障碍的水平； （2）大脑标记 炎症/免疫激活[基因阵列和免疫组织化学]； （3）脑组织中的生态表达 [qpcr]; （4）脑组织和脑源性外泌体[凝集素阵列和流式细胞术]的溶解度。 我们将利用糖基因新兴领域的最新进展和动物模型 与HIV相关的神经系统障碍，以阐明神经炎症之间的相关机制， 认知功能障碍和宿主免疫。我们的作品旨在创建一个新的范式来发现新颖的聚糖 - 可以针对旨在防止艾滋病毒患者持续存在的神经炎症的基于基于的互动 尽管病毒抑制。