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.

摘要 虽然严重急性呼吸综合征冠状病毒2（SARS-COV-2）被认为是一种呼吸道病原体， 在急性脑梗死期间，出现了无数的神经系统并发症，包括意识模糊、中风和神经肌肉疾病。 2019冠状病毒病。其病理生理机制尚不清楚，尽管证据主要表明 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， 研究这些病原体合并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PWH是否存在与认知和精神疾病相关的CNS病理风险增加， 健康并发症，如果他们也获得SARS-CoV-2。我们建议利用这一机会， 一个独特的早期ART治疗PWH队列的COVID-19后数据，具有纵向多模式CNS表型， 提供了关于SARS-CoV-2和HIV对大脑的综合影响的关键信息。 我们在泰国曼谷进行的纵向RV 254研究已经前瞻性地收集了超过13年的系统性 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 3特斯拉脑MRI在急性HIV期间和抑制性抗逆转录病毒治疗（ART）后的人。这些研究 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， CNS和精神健康结果。我们假设，已知的SARS-CoV-2的“二次打击”感染是 与神经免疫改变、血管损伤和神经元损伤相关-可能引发短暂或持久的 在接受良好治疗的威尔斯亲王医院中，中枢神经系统参数以及认知和精神健康结果的有害变化。 拟议的研究将分析RV 254参与者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COVID-19之后进行两次额外的访问。我们将收集比较样本， 来自对照RV 254参与者的数据--在相同时间间隔内观察到的PWH，无已知的COVID-19病史 而且没有COVID-19的抗体证据--根据年龄、性别和教育程度匹配的频率。 在目标1中，我们将确定接受ART治疗前后PWH患者CSF免疫、损伤和病毒学应答的变化。 COVID-19与对照组相比。在目的2中，我们将研究PWH的脑结构和功能改变 在COVID-19前后以及与对照组相比，在目标3中，我们将评估认知， 与对照组相比，在COVID-19前后接受ART的PWH患者的情绪和PASC症状及其关系 与目标1和目标2中的生物参数相匹配。在RV 254中，693名参与者中有125人记录了COVID- 在RV 254随访期间，我们已经收集了81名RV 254参与者的血液和临床数据 在COVID-19之前和之后因此，对COVID-19前后CNS参数的纵向分析， 在这个深度表型RV 254队列中比较非COVID-19对照将提供前所未有的洞察力， HIV和SARS-CoV-2共同感染对大脑的影响。