Longitudinal determination of nervous system consequences of SARS-CoV-2 in virologically suppressed people with HIV-1 treated in early infection

纵向测定 SARS-CoV-2 对早期感染治疗的病毒学抑制的 HIV-1 患者的神经系统影响

• 批准号: 10613789
• 负责人: Robert H Paul
• 金额: $ 324.99万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2025-09-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613789
• 关键词: 2019-nCoV; Acute; Affect; Age; Antibodies; Autoimmune; Biological; Biological Markers; Blood; Blood Vessels; Blood specimen; Brain; COVID-19; COVID-19 complications; COVID-19 impact; COVID-19 pandemic; Cerebrospinal Fluid; Clinical Data; Cognition; Cognitive; Collection; Confusion; Data; Diffusion Magnetic Resonance Imaging; Emotional; Encephalopathies; Exertion; Fatigue; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Gender; HIV; HIV-1; Headache; Heterogeneity; Image; Immune; Immune System Diseases; Immune system; Impaired cognition; Infection; Inflammation; Injury; Investigation; Lead; Magnetic Resonance Imaging; Measures; Mental Health; Modality; Moods; Morbidity - disease rate; Nervous system structure; Neuraxis; Neurocognitive; Neuroimmune; Neurologic; Neurologic Symptoms; Neuromuscular Diseases; Neuronal Injury; Neurons; Neuropathogenesis; Outcome; Participant; Pathogenesis; Pathogenicity; Pathology; Patients; Performance; Persons; Phenotype; Post-Acute Sequelae of SARS-CoV-2 Infection; Process; Publishing; Recording of previous events; Research; Rest; Risk; SARS-CoV-2 infection; SARS-CoV-2 negative; Sampling; Stroke; Structure; Symptoms; Syndrome; Testing; Thailand; Therapeutic Intervention; Time; Viral; Visit; Work; acute infection; antiretroviral therapy; base; biobank; brain magnetic resonance imaging; brain volume; cerebral atrophy; chronic infection; co-infection; cohort; coronavirus disease; depressive symptoms; design; executive function; experience; follow-up; imaging study; immune activation; improved; indexing; insight; longitudinal analysis; multimodality; nervous system disorder; neuroimaging; neuroinflammation; neuropsychiatry; pathogen; patient subsets; post-COVID-19; prospective; relating to nervous system; respiratory pathogen; response; time interval

Abstract Although severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) is considered a respiratory pathogen, myriad neurologic complications including confusion, stroke, and neuromuscular disorders manifest during acute COVID-19. The pathophysiological mechanisms are not well understood, although evidence primarily implicates immune dysfunction, including non-specific neuroinflammation and anti-neuronal autoimmune dysregulation. Multiple common mechanisms of neuropathogenesis are implicated in SARS-CoV-2 and HIV, warranting in-depth investigation of the central nervous system (CNS) effects of co-infection with these pathogens. An urgent question is whether the 38 million PWH worldwide are at increased risk of CNS pathology associated with cognitive and mental health complications if they also acquire SARS-CoV-2. We propose to leverage the opportunity to analyze pre- and post-COVID-19 data in a unique cohort of early ART treated PWH with longitudinal multimodal CNS phenotyping to provide key information regarding the combined effects of SARS-CoV-2 and HIV on the brain. Our longitudinal RV254 study based in Bangkok, Thailand has for over 13 years prospectively collected systematic neurologic, cognitive, and mood data, as well as blood samples and optional cerebrospinal fluid (CSF) and multimodal 3 Tesla brain MRI in people during acute HIV and after suppressive antiretroviral therapy (ART). These studies have led to transformative understanding of early HIV neuropathogenesis and the benefits of early ART intervention for CNS and mental health outcomes. We hypothesize that a ‘second hit’ infection with SARS-CoV-2 – known to be associated with neuroimmune alterations, vascular damage, and neuronal injury – may incite transient or lasting detrimental changes in CNS parameters and cognitive and mental health outcomes in well treated PWH. The proposed study will analyze samples and data collected in routine longitudinal assessment of RV254 participants prior to acquiring COVID-19, then from two additional visits after COVID-19. We will collect comparison samples and data from control RV254 participants -- PWH seen over the same time intervals with no known history of COVID-19 and with no antibody evidence of COVID-19-- frequency matched based on age, gender, and educational attainment. In Aim 1, we will identify changes in CSF immune, injury, and virologic responses in PWH on ART pre- and post- COVID-19 and in comparison to controls. In Aim 2, we will examine brain structural and functional alterations in PWH on ART pre- and post-COVID-19 and in comparison to controls. In Aim 3 we will assess the trajectory of cognitive, mood, and PASC symptoms in PWH on ART before and after COVID-19 compared to controls and their relationships with the biological parameters in Aims 1 & 2. In RV254, 125 of 693 total participants have had documented COVID- 19 during their RV254 follow up, and we have already collected blood and clinical data from 81 RV254 participants pre-and post-COVID-19. Thus, longitudinal analysis of CNS parameters from pre-and post-COVID-19 and comparison non-COVID-19 controls in this deeply phenotyped RV254 cohort will provide unprecedented insight into the effects of HIV and SARS-CoV-2 coinfection in the brain.

抽象的 尽管严重急性呼吸综合征冠状病毒 2 (SARS-COV-2) 被认为是呼吸道病原体， 急性发作期间会出现多种神经系统并发症，包括精神错乱、中风和神经肌肉疾病 新冠肺炎。尽管证据主要表明，其病理生理机制尚不清楚 免疫功能障碍，包括非特异性神经炎症和抗神经元自身免疫失调。 SARS-CoV-2 和 HIV 涉及多种常见的神经发病机制，值得深入研究 研究这些病原体共同感染对中枢神经系统（CNS）的影响。一个紧迫的问题是 全球 3800 万感染者罹患与认知和精神相关的中枢神经系统病理的风险是否增加 如果他们同时感染 SARS-CoV-2，则会出现健康并发症。我们建议利用这个机会来分析前期和后期 早期 ART 治疗的 PWH 的独特队列中的 COVID-19 后数据，采用纵向多模式 CNS 表型分析 提供有关 SARS-CoV-2 和 HIV 对大脑的综合影响的关键信息。 我们在泰国曼谷开展的纵向 RV254 研究已前瞻性收集了超过 13 年的系统数据 神经、认知和情绪数据，以及血液样本和可选的脑脊液 (CSF) 和多模式数据 3 急性 HIV 期间和抑制性抗逆转录病毒治疗 (ART) 后的特斯拉脑部 MRI。这些研究有 导致对早期 HIV 神经发病机制的变革性理解以及早期 ART 干预的益处 中枢神经系统和心理健康结果。我们假设 SARS-CoV-2 的“第二次打击”感染——已知是 与神经免疫改变、血管损伤和神经元损伤相关——可能会引起短暂或持久的 治疗良好的感染者中枢神经系统参数以及认知和心理健康结果的有害变化。 拟议的研究将分析 RV254 参与者的常规纵向评估中收集的样本和数据 在感染 COVID-19 之前，然后在感染 COVID-19 后另外两次就诊。我们将收集比较样本并 来自对照 RV254 参与者的数据——在相同时间间隔内观察到的 PWH，没有已知的 COVID-19 病史 并且没有 COVID-19 抗体证据——频率根据年龄、性别和教育程度进行匹配。 在目标 1 中，我们将确定 ART 前后 CSF 免疫、损伤和病毒学反应的变化。 COVID-19 以及与对照组的比较。在目标 2 中，我们将检查 PWH 中的大脑结构和功能变化 关于 COVID-19 前后的 ART 以及与对照的比较。在目标 3 中，我们将评估认知轨迹， COVID-19 前后接受 ART 治疗的感染者的情绪和 PASC 症状与对照组的比较及其关系 具有目标 1 和 2 中的生物参数。在 RV254 中，693 名参与者中的 125 名已记录了新冠病毒 - 19 在 RV254 随访期间，我们已经收集了 81 名 RV254 参与者的血液和临床数据 COVID-19 之前和之后。因此，对 COVID-19 前后的 CNS 参数进行纵向分析， 在这个深度表型 RV254 队列中比较非 COVID-19 对照将提供前所未有的见解 HIV 和 SARS-CoV-2 共同感染对大脑的影响。