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: 10599217
• 负责人: Mohamed Abdel Mohsen
• 金额: $ 84.38万
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599217
• 关键词: Acute; Affect; Animal Model; Anti-Inflammatory Agents; Antibodies; Antiinflammatory Effect; Attenuated; Behavior; Binding; Binding Proteins; Brain; Carbohydrates; Cells; Central Nervous System; 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; Macrophage; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Neuraminidase; Neurocognitive Deficit; Neurologic; Organ; Pathogenesis; Pattern; Physiological Processes; Plasma; Polysaccharides; Population; Prevalence; Process; Recovery; Role; Sialic Acids; Signal Transduction; Structure; Surface; TLR4 gene; Testing; Viral; Virus; Work; antiretroviral therapy; biological systems; brain tissue; comorbidity; exosome; humanized mouse; immune activation; inflammatory marker; inhibitor; 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：尽管抗逆转录病毒疗法 (ART) 得到广泛使用，但神经系统疾病的流行 炎症仍然很严重，据信涉及超过 40% 的 HIV+ 个体。这种炎症状态可能 导致认知功能障碍，影响日常功能并增加发病率和死亡率 ART 抑制的 HIV 感染者。然而，这种神经元背后的生理过程 炎症仍然知之甚少。该提案建立在我们正在进行的关于糖组学是否 循环糖蛋白和外泌体的改变在 HIV 相关神经系统疾病的发病机制中发挥作用 炎症和认知障碍。我们的初步数据表明，更高水平的亲 血浆、血浆外泌体和脑脊液 (CSF) 中的炎性低唾液酸化聚糖强烈 与 HIV+ ART 抑制个体的更严重的神经损伤相关。然而，无论糖 HIV 感染期间导致神经炎症的改变仍然未知。在这个项目中，我们将测试中央 假设存在糖组失调，特别是循环糖蛋白的唾液酸化低下 和外泌体，有助于神经炎症和 HIV 相关共病的发病机制 影响中枢神经系统（CNS）的疾病。 在目标 1 中，我们将确定低唾液酸化聚糖的神经炎症作用机制 在 ART 抑制的 HIV 感染期间。我们将使用高唾液酸化和低唾液酸化糖蛋白， 在离体模型中从患有神经功能障碍的 HIV+ ART+ 个体的血浆中分离出外泌体 在存在或不存在聚糖信号抑制剂的情况下，单核细胞活化/炎症和迁移的影响。在 目标 2，我们将检验以下假设：操纵循环唾液酸水平会影响神经系统 HIV相关神经损伤小鼠模型中的炎症和认知行为。我们将使用 EcoHIV小鼠模型（使用能够感染小鼠的嵌合HIV）最近被用作成功的 HIV发病机制和神经损伤模型。使用急性和长期感染 EcoHIV 的小鼠 （有或没有 ART），接受唾液酸纳米颗粒和唾液酸酶抑制剂的组合，或 裸纳米粒子作为对照，我们将评估：（1）认知障碍水平； (2) 大脑标志物 炎症/免疫激活[基因阵列和免疫组织化学]； (3)EcoHIV在脑组织中的表达 [qPCR]； (4) 脑组织和脑源性外泌体的唾液酸化[凝集素阵列和流式细胞术]。 我们将利用糖组学新兴领域和动物模型的最新进展 HIV相关的神经功能障碍，阐明神经炎症之间的相互关联机制， 认知功能障碍和宿主免疫。我们的工作旨在创建一个发现新型聚糖的新范例 基于相互作用，可以有针对性地预防艾滋病毒感染者持续存在的神经炎症 尽管病毒受到抑制。