Immunologic Profiles of Distinct Cognitive Trajectories in Adults with Perinatal HIV

围产期艾滋病毒成人独特认知轨迹的免疫学特征

• 批准号: 10190661
• 负责人: Payal Patel
• 金额: $ 17.91万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-11 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190661
• 关键词: 21 year old; Address; Adult; Affect; Age; Area; Biological; Biological Markers; Biology; Biometry; Birth; Brain; CD14 gene; CD8-Positive T-Lymphocytes; Cerebrospinal Fluid; Cerebrum; Child; Childhood; Clinical; Cognition; Cognitive; Communicable Diseases; Complex; Connecticut; Cross-Sectional Studies; Cytometry; Data; Development; Diagnosis; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Doctor of Philosophy; Enrollment; FCGR3B gene; Flow Cytometry; Foundations; Frequencies; Funding; Future; Goals; HIV; HIV-1; HIV-associated cognitive impairment; HLA-DR Antigens; Health; Heterogeneity; Immune; Immune response; Immunologic Markers; Immunologics; Impaired cognition; Impairment; Individual; Intervention; Knowledge; Light; Link; Long-Term Survivors; Longitudinal cohort study; Mentors; Mentorship; Methods; Modeling; Morbidity - disease rate; Nervous System Trauma; Neuraxis; Neurodevelopmental Impairment; Neurologic; Neurological outcome; Neurologist; Neuronal Injury; Outcome; Participant; Pathogenesis; Perinatal; Peripheral; Plasma; Population; Prevalence; Prevention; Productivity; Prospective Studies; Protocols documentation; Psyche structure; RNA; Research; Risk Factors; Southeastern Asia; Subgroup; T-Cell Activation; Techniques; Time; Training; Viral; Viral Load result; Youth; age group; analytical method; antiretroviral therapy; base; cognitive performance; cohort; comorbidity; early adolescence; experience; imaging biomarker; immune activation; improved; longitudinal analysis; monocyte; mortality; neuroAIDS; neurocognitive test; neurofilament; neuroimaging; novel; outcome forecast; outcome prediction; perinatal HIV; peripheral blood; preservation; prevent; resilience; tool; trafficking; treatment effect; trend; viral RNA; white matter; young adult

Over 60,000 young adults are living with HIV in the US today, many of whom acquired HIV at birth. This group of adults with perinatally acquired HIV (pHIV) has not seen improvements in the prevalence of HIV- related co-morbidities, including poor cognitive outcomes. Despite this trend, little is known about the prognosis and pathogenesis of pHIV-related cognitive impairment in adulthood. Cognitive dysfunction occurs in up to half of individuals living with HIV, and is directly associated with immune activation in adults with horizontally acquired HIV (hHIV). In contrast, CD8+ T-cell and monocyte activation in our cohort of children with pHIV in Southeast Asia correlates with better cognitive scores suggesting an adapted immune-host response in those who are long-term survivors of pHIV. This adapted state has not been well studied. The goal of our proposed study is to address key gaps in our understanding of 1) cognitive trajectories and 2) biomarkers of cognitive resilience in adults with pHIV, through a recently initiated longitudinal cohort study of adults with pHIV in Connecticut. We will evaluate 1) cognitive performance and 2) interactions between peripheral and cerebrospinal fluid (CSF) immunologic markers, neuroimaging and cognition using a novel analytic method, group based trajectory modeling. This study will determine the prognosis of cognitive impairment and further characterize the biologic underpinnings of cognitive resilience as potential neuroprotective targets in adults with pHIV. The candidate is a pediatric neurologist with specialized training in neuro-infectious diseases. Dr. Patel is committed to improving our understanding of the pathogenesis of and treatment for poor neurologic outcomes following pHIV. The proposal will capitalize on Dr. Patel's prior training and mentored research experience in group based trajectory analysis of longitudinal cognitive data in children with pHIV, while enabling her to build expertise in 1) flow cytometry methods and analyses, 2) utilizing diffusion tensor imaging as a research tool, and 3) dual trajectory analysis, a complex modeling technique to assess contemporaneous changes in longitudinally acquired biomarker and cognitive data. Dr. Patel has assembled a mentorship committee comprised of leaders in the pathogenesis of neurologic injury in adults with hHIV (Serena Spudich, MD, primary mentor), biomarkers of disease progression in pHIV (Elijah Paintsil, MBChB, co-mentor), and biostatistics and imaging markers of cognitive impairment in pHIV (Robert Paul, PhD, co-mentor). The knowledge and experience gained from this proposal will allow Dr. Patel to successfully compete for R01 funding to further evaluate the pathogenesis and prevention of pHIV-related neurologic morbidity. Her future R01 applications will focus on cerebral HIV compartmentalization in adults with pHIV and analyzing cellular subsets identified in the proposed study as linked to cognitive resilience in CSF using mass cytometry.

今天，美国有超过60，000名年轻人感染艾滋病毒，其中许多人在出生时就感染了艾滋病毒。 这组患有围产期获得性艾滋病毒（pHIV）的成年人的患病率没有改善， 艾滋病毒相关的合并症，包括认知结果差。尽管有这种趋势，但人们对 成人期pHIV相关认知障碍的预后和发病机制。认知功能障碍 发生在多达一半的艾滋病毒感染者中，并与免疫激活直接相关， 成人横向获得性艾滋病毒（hHIV）。相比之下，在我们的研究中， 东南亚pHIV感染儿童队列与更好的认知评分相关，这表明 适应性免疫宿主反应在那些谁是pHIV的长期幸存者。这种适应性的状态并没有 被好好研究过了。我们提出的研究的目标是解决我们理解的关键差距， 1)认知轨迹和2）pHIV成年人认知恢复力的生物标志物，通过 最近在康涅狄格州启动了一项对pHIV成年患者的纵向队列研究。我们将评估1） 认知能力和2）外周和脑脊液（CSF）免疫学之间的相互作用 标记，神经成像和认知使用一种新的分析方法，基于组的轨迹建模。 这项研究将确定认知障碍的预后，并进一步表征生物学特性。 作为pHIV成年患者潜在神经保护靶点的认知弹性基础。 候选人是一名儿科神经科医生，接受过神经感染性疾病的专门培训。博士 帕特尔致力于提高我们对贫困的发病机制和治疗的理解。 pHIV后的神经学结局。该提案将利用帕特尔博士先前的培训， 在基于组的纵向认知数据轨迹分析中的指导研究经验， pHIV感染儿童，同时使她能够在1）流式细胞术方法和 分析，2）利用扩散张量成像作为研究工具，3）双轨迹分析， 复杂的建模技术，以评估纵向获得的 生物标志物和认知数据。帕特尔博士召集了一个导师委员会 在成人hHIV神经损伤的发病机制中（Serena Spudich，医学博士，主要导师）， pHIV中疾病进展的生物标志物（Elijah Paintsil，MBChB，共同导师）和生物统计学， pHIV中认知障碍的成像标志物（Robert Paul，PhD，共同导师）。的知识和 从该提案中获得的经验将使Patel博士能够成功地竞争R01资金， 进一步评估pHIV相关神经系统疾病的发病机制和预防。未来R01 应用将集中在pHIV成人的大脑HIV区室化和分析细胞 在拟议的研究中确定的子集与使用质谱细胞术的CSF中的认知恢复力有关。