Understanding the cellular basis for persistent immune activation in the central nervous system during virologically suppressed HIV

了解病毒学抑制艾滋病毒期间中枢神经系统持续免疫激活的细胞基础

• 批准号: 10000209
• 负责人: Shelli Farhadian
• 金额: $ 19.07万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-25 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10000209
• 关键词: Adult; Affect; Big Data; Bioinformatics; Biological; Biological Markers; Blood; Blood Cells; Cell Lineage; Cells; Cerebrospinal Fluid; Chronic; Communicable Diseases; Communities; Computer Analysis; Cytometry; Data; Dendritic Cells; Detection; Disease; Doctor of Philosophy; Exhibits; Face; Flow Cytometry; Future; Gene Expression; Gene Expression Profile; Gene Proteins; Genetic Transcription; Genomic approach; Genomics; Goals; HIV; HIV Infections; HIV therapy; HIV-1; Head; Immune; Immune system; Immunology; Impairment; Individual; Infection; Inflammation; Light; Long-Term Effects; Mediating; Mediator of activation protein; Mentors; Mentorship; Methods; Microglia; Morbidity - disease rate; Myelogenous; Myeloid Cells; Neopterin; Nerve Degeneration; Neuraxis; Neurocognitive Deficit; Neurodegenerative Disorders; Neurologic; Neurologic Effect; Neuronal Injury; Neurons; Participant; Pathway interactions; Patients; Physicians; Plasma; Population; Prevalence; Principal Investigator; Process; RNA; Research; Research Personnel; Residual state; Scientist; Specific qualifier value; Techniques; Therapeutic Intervention; Training; Transcript; Viral; Virus; Virus Diseases; Virus Replication; antiretroviral therapy; base; career; cell type; computational pipelines; genomic data; genomic tools; immune activation; interest; monocyte; neuroAIDS; neurocognitive disorder; neurofilament; neurogenetics; neuroimaging; neuroimmunology; new therapeutic target; novel; patient oriented research; prevent; programs; single-cell RNA sequencing; skills; targeted treatment; therapy development; tool; virology; volunteer

PROJECT SUMMARY/ABSTRACT Despite major advances in combination antiretroviral therapy (ART), adults living with HIV infection continue to suffer from high rates of morbidities associated with chronic immune activation, including neurocognitive impairment. Indeed, the prevalence of neurocognitive disorders in adults with HIV remains unchanged in the ART era: an estimated 50% of adults with virologically suppressed HIV have some form of neurocognitive impairment. Understanding the cellular basis for persistent CNS immune activation is thus critical for reducing neurological morbidities in the growing population of adults with HIV on treatment. Studies to date have focused on CSF biomarkers or CSF immune cell flow cytometry, but these studies are limited by the need to pre-specify markers of interest, thus missing the opportunity to identify de novo cell populations that may drive CNS immune activation and downstream neuronal damage, including rare myeloid subsets. The candidate has developed a reliable pipeline to profile single cerebrospinal fluid (CSF) immune cells at the transcriptional level, and has successfully used this technique to identify a rare cellular subset in CSF that presents a gene expression pattern consistent with disease-associated microglia. The research proposed here will utilize these state of the art methods to analyze CSF and blood from adult volunteers with and without HIV disease, to characterize novel or rare cell populations in the CNS during treated, suppressed HIV. Defining CNS immune activation in exquisite detail, including cellular populations that distinguish HIV infection during ART, has the potential to provide critical targets for therapeutic intervention for residual neurologic impairment during HIV treatment. The principal investigator is a physician scientist, with specialized training in Neuroinfectious disease and a PhD in Neurogenetics. Her career goal is to become an independent investigator studying neurological sequelae of infectious diseases, with a special focus on neurological effects of HIV infection. The proposed K23 training plan will provide the candidate with mentorship and coursework to build specific expertise necessary to execute the proposed project and become independent in her field, including expertise in: 1. Immunology and Neuro-infectious diseases 2. “Big data” genomics and associated computational analysis, and 3. Skills necessary to head an independent, patient-oriented research program. To achieve these goals, Dr. Farhadian has assembled a primary mentoring team consisting of experts in Neuro-HIV, Neuroimmunology, and Bioinformatics.

项目总结/摘要 尽管联合抗逆转录病毒疗法（ART）取得了重大进展，但感染艾滋病毒的成年人继续受到感染。 患有与慢性免疫激活相关的高发病率，包括神经认知 损伤事实上，在2010年，艾滋病毒感染者中神经认知障碍的患病率保持不变。 ART时代：估计50%的病毒学抑制HIV的成年人有某种形式的神经认知障碍。 损伤因此，了解持续性CNS免疫激活的细胞基础对于减少 在接受治疗的艾滋病毒感染者中，神经系统疾病的发病率不断增加。迄今为止， 集中于CSF生物标志物或CSF免疫细胞流式细胞术，但这些研究受到以下需要的限制： 预先指定感兴趣的标志物，从而错过了识别可能驱动细胞增殖的从头细胞群的机会。 CNS免疫激活和下游神经元损伤，包括罕见的骨髓亚群。 候选人已经开发出一种可靠的管道，可以在24小时内对单个脑脊液（CSF）免疫细胞进行分析。 转录水平，并已成功地使用这种技术，以确定一个罕见的细胞亚群在CSF中， 呈现出与疾病相关的小胶质细胞一致的基因表达模式。这里提出的研究 将利用这些最先进的方法来分析CSF和血液从成人志愿者与非艾滋病毒 疾病，以表征治疗，抑制HIV期间CNS中的新的或罕见的细胞群。限定 CNS免疫激活的精致细节，包括区分HIV感染的细胞群， ART有可能为残余神经功能缺损的治疗干预提供关键靶点 在艾滋病治疗期间。 主要研究者是一名医生科学家，接受过神经感染性疾病的专门培训， 神经遗传学博士她的职业目标是成为一名研究神经学的独立调查员 传染病后遗症，特别关注艾滋病毒感染的神经影响。拟议 K23培训计划将为候选人提供指导和课程，以建立特定的专业知识 必要的执行拟议的项目，并成为独立的领域，包括专业知识：1。 免疫学和神经传染病2.“大数据”基因组学和相关的计算分析，以及 3.领导一个独立的，以病人为导向的研究项目所需的技能。为了实现这些目标，博士。 Farhadian组建了一个主要的指导团队，由神经艾滋病毒，神经免疫学， 和生物信息学。