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

项目摘要/摘要 尽管进行了抑制性抗逆转录病毒治疗，但HIV(PWH)患者仍存在神经精神并发症。二 PWH常见的致残条件是认知障碍(CI)和严重抑郁障碍(MDD)。 然而，PWH患者中枢神经系统(CNS)功能障碍的病理生理学导致这些 情况仍然难以捉摸，因此是艾滋病毒的一个高度优先主题。活化的外周血液的运输 单个核细胞(PBMC)，特别是CD14 CD16单核细胞进入病毒抑制(VS)-PWH的脑内 已经出现了神经炎症的推定因素。我们建议检验我们的假设，即VS-PWH将 血脑屏障(BBB)的破坏是否与靶向、可溶循环有关 细胞因子/趋化因子与PBMC表面蛋白上调后者与紧密连接相互作用， 黏附连接蛋白，削弱血脑屏障，促进PBMC渗入脑内。BBB中断可能 促进持续性神经炎症和神经元活动改变，从而导致神经精神后遗症。至 为此，我们建议横断面成像和腰椎穿刺术来评估BBB的完整性，并提供基线和 纵向神经精神评估和血液采样。350人感染威斯康星病毒，100人未感染艾滋病毒(艾滋病毒-) 将从约翰霍普金斯医院内的约翰斯·G·巴特利特诊所和 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和其 对神经精神疾病的贡献(目标1)。我们将使用一种新的、非对比的方法来评估血脑屏障的完整性 使用water-extraction-with-phase-contrast-arterial-spin-tagging的磁共振成像技术 (WEPCAST)，以确定血脑屏障对水的渗透性，从而对小分子的渗透性。我们已经把这个展示给 对轻度认知障碍的血脑屏障变化要敏感，这是阿尔茨海默病的前兆。此外，我们有 发现WEPCAST具有良好的耐受性，并且在VS-PWH中很好地估计了PS值。第二，我们的目标是评估 循环可溶性标志物、PBMC相关标志物与血脑屏障通透性的关系 分子，这些分子共同可能促进潜流进入大脑(目标2)。我们针对的是与 激活的PBMCs通过血脑屏障向脑内迁移的增加，在那里它们可能对神经元起作用 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 将完整的血脑屏障模型转化为血脑屏障对小分子的渗透性的PBMC(目标3)。我们的创新与 实时评估体外细胞功能(BBB模型)和体内BBB测量(WEPCAST)。之后 5年的资助，R01将促进我们对BBB完整性和相关PBMC迁移到 VS-PWH的大脑，这可能导致神经炎症和相关的神经精神负担。这些 这些发现将为开发治疗方法的下一步提供信息，以最大限度地减少PBMC对 VS-PWH的神经炎症。

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.