Immune dynamics shaping blood brain barrier integrity in virally suppressed people with HIV

免疫动力学塑造病毒抑制的艾滋病毒感染者血脑屏障的完整性

• 批准号: 10264153
• 负责人: Jennifer Marie Coughlin
• 金额: $ 71.17万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10264153
• 关键词: ALCAM gene; Address; Adherens Junction; Affect; Age; Albumins; Alzheimer' s Disease; Area; Baltimore; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Platelets; Blood specimen; Brain; Brain scan; CCL19 gene; CCL2 gene; CCL23 gene; CD14 gene; CX3CL1 gene; CXCL12 gene; CXCL9 gene; Caliber; Caring; Cell Surface Proteins; Cell physiology; Cells; Cerebrospinal Fluid; Chronic; Clinic; Cognition; Cognitive; Communities; Development; FCGR3B gene; Fractalkine; Frequencies; Functional disorder; Funding; HIV; HIV Infections; Health; Hospitals; Image; Imaging Device; Imaging Techniques; Immune; Impaired cognition; Individual; Infection; Infrastructure; Interleukin-6; Investigation; Link; Lymphocyte; Magnetic Resonance Imaging; Major Depressive Disorder; Measures; Membrane Proteins; Memory impairment; Mental Health; Methods; Modeling; Molecular; Molecular Weight; NIH Office of AIDS Research; Neuraxis; Neurons; Neurotoxins; Outcome; Peripheral Blood Mononuclear Cell; Phase; Phenotype; Play; Proteins; Public Health; Research; Role; Sampling; Serum Albumin; Shapes; Spinal Puncture; Strategic Planning; Supporting Cell; Surface; TNF gene; Techniques; Testing; Therapeutic; Tight Junctions; Time; Up-Regulation; Vascular Endothelial Growth Factors; Vascular Endothelium; Viral; Water; antiretroviral therapy; blood-brain barrier disruption; blood-brain barrier permeabilization; cell motility; chemokine; cognitive testing; cytokine; dalton; experience; in vivo; inflammatory marker; innovation; migration; mild cognitive impairment; monocyte; neuroinflammation; neuropsychiatry; new therapeutic target; novel; recruit; small molecule; therapeutic development; trafficking

PROJECT SUMMARY/ABSTRACT Neuropsychiatric complications persist in people with HIV (PWH) despite suppressive antiretroviral therapy. Two common, often disabling conditions in PWH are cognitive impairment (CI) and major depressive disorder (MDD). However, the pathophysiology of central nervous system (CNS) dysfunction in PWH that results in these conditions remain elusive and thus a HIV high priority topic. The trafficking of activated peripheral blood mononuclear cells (PBMCs), specifically CD14+CD16+ monocytes, into brains of virally suppressed (VS)-PWH has emerged a putative contributor to neuroinflammation. We propose to test our hypothesis that VS-PWH will have blood brain barrier (BBB) disruption mechanistically linked to targeted, circulating soluble cytokines/chemokines and upregulation of PBMC surface proteins. The latter interact with tight junction and adherens junction proteins to weaken the BBB, promoting PBMC diapedesis into brain. BBB disruption may promote persistent neuroinflammation and altered neuronal activity contributing to neuropsychiatric sequela. To this end, we propose cross-sectional imaging and lumbar puncture to assess BBB integrity, with baseline and longitudinal neuropsychiatric assessments and blood sampling. 350 VS-PWH and 100 HIV-uninfected (HIV-) individuals will be recruited from the Johns G. Bartlett Clinic within the Johns Hopkins Hospital and in the surrounding Baltimore community. First, we aim to assess the effects of well-controlled HIV on the BBB and its contribution to neuropsychiatric conditions (Aim 1). We will assess BBB integrity using a novel, non-contrast magnetic resonance imaging technique that uses water-extraction-with-phase-contrast-arterial-spin-tagging (WEPCAST), to determine BBB permeability to water, and thereby to small molecules. We have shown this to be sensitive to BBB change in mild cognitive impairment, a precursor to Alzheimer’s disease. Moreover, we have found WEPCAST to be well-tolerated and estimate PS values well in VS-PWH. Second, we aim to assess the relationship between circulating soluble markers, PBMC-associated markers, and BBB permeability to small molecules, which collectively may promote diapedesis into brain (Aim 2). We target factors implicated in a heightened transmigration of activated PBMCs across the BBB into brain, where they may contribute to neuronal damage and neuropsychiatric burden in VS-PWH. Finally, we aim to examine the relationship of activated PBMCs that transmigrate an intact BBB model to BBB permeability to small molecules (Aim 3). We innovate with the real-time assessment of ex vivo cellular function (BBB model) and in vivo BBB measures (WEPCAST). After 5 years of funding, this R01 will advance our understanding of BBB integrity and related PBMC migration into the brains of VS-PWH, which may contribute to neuroinflammation and related neuropsychiatric burden. These findings will inform next steps in the development of therapeutic approaches to minimize PBMC contribution to neuroinflammation in VS-PWH.

项目总结/摘要 尽管进行了抑制性抗逆转录病毒治疗，但HIV感染者（PWH）的神经精神并发症仍持续存在。两 PWH中常见的、常常致残的病症是认知障碍（CI）和重度抑郁症（MDD）。 然而，PWH中中枢神经系统（CNS）功能障碍的病理生理学导致这些 条件仍然难以捉摸，因此是艾滋病毒的高度优先主题。活化外周血的运输 单核细胞（PBMC），特别是CD 14 + CD 16+单核细胞，进入病毒抑制（VS）-PWH的脑中。 被认为是神经炎症的诱因我们建议测试我们的假设，即VS-PWH将 血脑屏障（BBB）破坏机制与靶向，循环可溶性 细胞因子/趋化因子和PBMC表面蛋白的上调。后者与紧密连接相互作用 粘附连接蛋白减弱血脑屏障，促进PBMC向脑内渗出。BBB破坏可能 促进持续的神经炎症和改变的神经元活动，从而导致神经精神后遗症。到 为此，我们建议采用横断面成像和腰椎穿刺来评估血脑屏障的完整性， 纵向神经精神评估和血液采样。350名VS-PWH患者和100名未感染艾滋病毒的患者（艾滋病毒-） 将从约翰·G。巴特利特诊所在约翰霍普金斯医院和 在巴尔的摩社区周围。首先，我们的目标是评估控制良好的艾滋病毒对血脑屏障及其 对神经精神疾病的贡献（目标1）。我们将使用一种新的非造影剂， 使用相位对比动脉自旋标记水提取的磁共振成像技术 （WEPCAST），以确定BBB对水的渗透性，从而对小分子的渗透性。我们已经向 对轻度认知障碍的BBB变化敏感，这是阿尔茨海默病的前兆。而且我们 发现WEPCAST耐受性良好，在VS-PWH中可很好地估计PS值。第二，我们的目标是评估 循环可溶性标志物、PBMC相关标志物和血脑屏障对小细胞的通透性之间的关系 分子，其共同地可促进渗出进入脑（Aim 2）。我们针对的是 活化的PBMC穿过BBB进入脑的迁移增加，在脑中它们可能有助于神经元的增殖。 VS-PWH的损害和神经精神负担。最后，我们的目标是检查激活的关系 将完整BBB模型的PBMC迁移至BBB对小分子的渗透性（目的3）。我们创新与 离体细胞功能的实时评估（BBB模型）和体内BBB测量（WEPCAST）。后 经过5年的资助，该R 01将促进我们对BBB完整性和相关PBMC迁移的理解， VS-PWH的大脑，这可能有助于神经炎症和相关的神经精神负担。这些 研究结果将为下一步开发治疗方法提供信息，以最大限度地减少PBMC对肿瘤的贡献。 VS-PWH中的神经炎症。