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)被认为是呼吸道病原体， 无数的神经系统并发症，包括精神错乱、中风和神经肌肉疾病，在急性发作期间表现出来 新冠肺炎。其病理生理机制尚不清楚，尽管主要证据表明 免疫功能障碍，包括非特异性神经炎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 研究合并感染这些病原体对中枢神经系统(CNS)的影响。一个紧迫的问题是 全球3800万PWH患者患中枢神经系统疾病的风险是否与认知和心理有关 如果他们也感染了SARS-CoV-2，就会出现健康并发症。我们建议利用这一机会分析预售和 新冠肺炎后的数据在一个独特的早期抗逆转录病毒治疗的PWH队列中使用纵向多模式中枢神经系统表型分析 提供有关SARS-CoV-2和艾滋病毒对大脑的综合影响的关键信息。 我们设在泰国曼谷的纵向RV254研究已经前瞻性地收集了超过13年的系统 神经学、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急性HIV期间和抑制性抗逆转录病毒治疗(ART)后人群的特斯拉脑磁共振成像。这些研究已经 导致了对早期HIV神经发病机制和早期ART干预的好处的革命性理解 中枢神经系统和心理健康结果。我们推测，感染SARS-CoV-2病毒的第二次袭击是已知的 与神经免疫改变、血管损伤和神经元损伤相关--可能引发一过性或持续性 经过良好治疗的PWH患者的中枢神经系统参数以及认知和心理健康结果中的有害变化。 拟议的研究将分析在RV254参与者的常规纵向评估中收集的样本和数据 在收购新冠肺炎之前，则从新冠肺炎之后的另外两次访问开始。我们将收集比较样本并 来自对照组RV254参与者的数据--在相同时间间隔内看到的PWH，没有已知的新冠肺炎历史 而且没有新冠肺炎的抗体证据--根据年龄、性别和教育程度匹配的频率。 在目标1中，我们将确定抗逆转录病毒治疗前后重症肝炎患者脑脊液免疫、损伤和病毒学反应的变化。 并与新冠肺炎控件进行了比较。在目标2中，我们将研究PWH的脑结构和功能变化。 在新冠肺炎之前和之后的ART以及与对照组的比较。在目标3中，我们将评估认知的轨迹， 新冠肺炎治疗前后重症肝炎患者的情绪、PASC症状与对照组及其关系的比较 与AIMS 1和AIMS 2中的生物学参数进行比较。在RV254中，693名参与者中有125人记录了COVID- 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 在新冠肺炎之前和之后。因此，对新冠肺炎前后的中枢神经系统参数进行了纵向分析 在这个表型很深的RV254队列中比较非新冠肺炎控件将提供前所未有的洞察力 HIV和SARS-CoV-2混合感染对脑部的影响