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

项目总结：尽管抗逆转录病毒治疗（ART）的广泛使用，神经系统疾病的患病率仍在上升。 炎症仍然很高，据信涉及>40%的HIV+个体。这种炎症状态很可能 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，这种神经元的生理过程- 炎症仍然知之甚少。这项建议建立在我们正在进行的关于糖代谢是否 循环糖蛋白和外泌体的改变在HIV相关的神经系统疾病的发病机制中起作用。 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抑制个体中更严重的神经损伤相关。然而，糖组学是否 在HIV感染期间，改变驱动神经炎症仍然是未知的。在这个项目中，我们将测试中央 宿主糖组失调，特别是循环糖蛋白低唾液酸化假说 和外泌体，有助于神经炎症和艾滋病毒相关的共- 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的机制 在抗逆转录病毒治疗抑制艾滋病毒感染期间。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，从具有神经损伤的HIV+ ART+个体的血浆中分离的外来体 在存在或不存在聚糖信号传导抑制剂的情况下，单核细胞活化/炎症和迁移。在 目的2，我们将测试这一假设，即操纵循环唾液酸水平影响神经元功能。 炎症和认知行为在HIV相关神经损伤小鼠模型。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的模型。使用急性和慢性EcoHIV感染小鼠 (with并且没有ART），其接受唾液酸纳米颗粒和唾液酸酶抑制剂的组合，或者 裸纳米颗粒作为对照，我们将评估：（1）认知障碍的水平;（2） 炎症/免疫激活[基因阵列和免疫组织化学];（3）脑组织中EcoHIV的表达 [qPCR];和（4）脑组织和脑源性外来体的唾液酸化[凝集素阵列和流式细胞术]。 我们将利用糖组学新兴领域的最新进展和动物模型， HIV相关的神经损伤，以阐明神经炎症， 认知功能障碍和宿主免疫我们的工作旨在为发现新型聚糖创造一个新的范例- 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 尽管病毒被抑制了

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.