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: 10118741
• 负责人: Jennifer Marie Coughlin
• 金额: $ 74.16万
• 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/10118741
• 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.

项目摘要/摘要 艾滋病毒（PWH）欲望抑制性抗逆转录病毒疗法的神经精神并发症持续存在。二 常见的，通常在PWH中致残的条件是认知障碍（CI）和重度抑郁症（MDD）。 但是，PWH中中枢神经系统（CNS）功能障碍的病理生理导致这些 条件仍然难以捉摸，因此是HIV高优先级主题。贩运活化的外周血 单核细胞（PBMC），特别是CD14+ CD16+单核细胞，变成几乎被抑制的大脑（VS）-PWH 已经成为神经炎症的推定贡献者。我们建议检验我们的假设，即VS-PWH将会 具有血液脑屏障（BBB）的机械障碍（BBB）与有针对性的，循环固体相关 细胞因子/趋化因子和PBMC表面蛋白的上调。后者与紧密的连接点相互作用， 粘附连接蛋白可削弱BBB，从而促进PBMC二尿中的脑部。 BBB破坏可能 促进持续性神经炎症和改变神经精神续集的神经元活性。到 我们提出了这一目标，提出横截面成像和腰椎穿刺，以评估BBB完整性，基线和 纵向神经精神病学评估和血液采样。 350 vs-PWH和100 HIV未感染（HIV-） 个人将从约翰·霍普金斯医院的约翰·G·巴特利特诊所和 周围的巴尔的摩社区。首先，我们旨在评估良好控制的艾滋病毒对BBB及其ITS的影响 对神经精神疾病的贡献（AIM 1）。我们将使用新颖的非对比度评估BBB的完整性 磁共振成像技术，该技术使用与相 - 对比度 - 旋转旋转标记的水甲 （WEPCAST​​），确定BBB对水的渗透性，从而确定小分子。我们已将其显示为 对轻度认知障碍的BBB变化敏感，这是阿尔茨海默氏病的前体。而且，我们有 发现Wepcast在VS-PWH中良好且估计的PS值良好。第二，我们旨在评估 循环实心标记，与PBMC相关的标记和BBB渗透性之间的关系 分子可以统称会促进大脑的尿（目标2）。我们的目标因素与 BBB跨BBB激活的PBMC的迁移增加了大脑，它们可能有助于神经元 VS-PWH中的损害和神经精神伯恩。最后，我们旨在检查激活的关系 将完整的BBB模型传播到BBB渗透率向小分子传递的PBMC（AIM 3）。我们无效 体内细胞功能（BBB模型）和体内BBB测量（WEPCAST​​）的实时评估。后 5年的资金，此R01将使我们对BBB完整性和相关PBMC迁移的了解 VS-PWH的大脑可能有助于神经炎症和相关的神经精神伯恩。这些 调查结果将为理论方法开发的下一步提供信息，以最大程度地减少PBMC的贡献 VS-PWH中的神经炎症。