Gamma delta T cells promote inflammation in aviremic HIV infection and normal aging

γ δ T 细胞促进无病毒血症 HIV 感染和正常衰老中的炎症

基本信息

批准号：
10655453
负责人：
Jennifer E Snyder-Cappione
金额：
$ 73.27万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10655453
关键词：
Age Aging Algorithms Architecture Automobile Driving Bioinformatics Biological Biopsy Blood Cardiovascular Diseases Cell Culture Techniques Cell Lineage Cell Separation Cell physiology Cells Cessation of life Chronic Circulation Colon Color Cross-Sectional Studies Cytometry Data Data Analyses Data Set Dementia Development Disease Elderly Ensure Epithelial Cells Epithelium Exhibits Exposure to Flow Cytometry Gastrointestinal tract structure Geriatric Assessment Glean HIV HIV Enteropathy HIV Infections Image Immune In Vitro Individual Inflammaging Inflammation Inflammatory Intestinal permeability Intestines Introns Link Longitudinal Studies Malignant Neoplasms Marker Discovery Measurement Measures Movement Multivariate Analysis Osteoporosis Outcome Outcome Measure Pathologic Processes Peripheral Blood Mononuclear Cell Persons Phenotype Plasma Population Proteomics RNA Reporting Role Sampling Site Small Intestines Sorting Stroke T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Testing Tight Junctions Tissues Viral Viral Load result Visualization aged antagonist bone loss cohort comorbidity cytokine cytotoxicity detection assay experimental study frailty gastrointestinal human old age (65+)in vitro Assay inflammatory marker inhibitor innovation insight intestinal barrier intestinal epithelium latent HIV reservoir microbial products monolayer mortality multiplex detection normal aging novel novel therapeutic intervention novel therapeutics prevent prospective receptor response systemic inflammatory response γδ T cells

项目摘要

ABSTRACT Even with successful viral control, HIV-infected individuals exhibit co-morbidities associated with older age, including osteoporosis, stroke, dementia, and cancer. In aviremic HIV+ individuals and the general geriatric population, age-associated diseases and mortality correlate with plasma markers of inflammation and intestinal permeability. The gut is a major reservoir of latently HIV-infected cells, and HIV enteropathy, defined as pathologic processes in the small intestine and colon, is a hallmark of HIV infection. Our preliminary data implicate gamma delta T cells as an inflammatory driver in ART-suppressed HIV infection and with normal aging. gamma delta T cells are a non-conventional T cell lineage that comprise ≤10% of circulating T cells yet are found in considerably higher proportions in the epithelium of the intestine. Also, there is evidence that this unique T cell population regulates intestinal barrier function during normal conditions, and that gamma delta T pro-inflammatory activity causes damage at epithelial sites and to epithelial barriers. Therefore, we hypothesize that with virally suppressed HIV infection and with normal aging, gastrointestinal gamma delta T cells are stimulated via directly harboring HIV and/or exposure to inflammatory factors and this aberrant activation leads to breakdown of tight junctions of the intestinal epithelial barrier, causing increased release of microbial products and inflammatory gamma delta T cells into the circulation. Further, we predict that aged gamma delta T cells exhibit functional profiles skewed towards inflammatory cytokines/cytotoxicity in response to either direct HIV infection and/or stimulatory factors. In this application, we propose to test these hypotheses using advanced and innovative approaches, including 25-color flow cytometry, 31-color imaging mass cytometry of recto-sigmoid biopsies, 19- and 33-plex analyses of plasma and cell culture supernatants, respectively, and multiple algorithms for multivariate analysis of collected datasets. Our bioinformatic data analysis plan will enable identifying novel gamma delta T cell subsets and parsing the differential impacts of age with and without HIV infection. In Aim 1 we will perform a cross-sectional study of our HIV and Aging cohort to determine the links between circulating gamma delta T cell subsets, plasma inflammatory and intestinal permeability markers, and intestinal architecture and cellular composition. In Aim 2 we will determine the temporal links between gamma delta T cell subsets, plasma markers, and the onset and/or progression of geriatric outcomes via a longitudinal study of older subjects with and without ART-suppressed HIV. In Aim 3, we will perform in vitro assays to determine how age and HIV infection impact gamma delta T cell functions, including the capacity to breakdown intestinal epithelial cell monolayers. We predict that our proposed experiments will identify the biological mechanisms that drive the increased systemic inflammation and age-associated comorbidities in both aviremic HIV+ individuals and the general geriatric population; such insight could lead to the development of novel therapeutics to reduce ‘inflamm-aging’-associated diseases and deaths.

抽象的即使成功控制了病毒，艾滋病毒感染者也会表现出与老年相关的并发症，包括骨质疏松症、中风、痴呆症和癌症。人口、年龄相关疾病和死亡率与炎症和肠道的血浆标志物相关肠道是潜在的 HIV 感染细胞的主要储存库，HIV 肠病定义为我们的初步数据显示，小肠和结肠的病理过程是 HIV 感染的标志。表明 γδT 细胞是 ART 抑制的 HIV 感染和正常情况下的炎症驱动因素 γ δ T 细胞是一种非常规 T 细胞谱系，占循环 T 细胞的比例≤10%，但仍存在于衰老过程中。此外，有证据表明这种独特的 T 细胞在肠道上皮中的比例相当高。正常情况下，人群调节肠道屏障功能，并且 γ δ T 促炎活性导致上皮部位和上皮屏障损伤，因此，我们通过病毒捕获了这一点。抑制 HIV 感染，并且在正常衰老的情况下，胃肠道 γ δ T 细胞通过直接窝藏受到刺激 HIV 和/或暴露于炎症因子，这种异常激活会导致紧密连接的破坏肠上皮屏障，导致微生物产物和炎症性 γ δ T 细胞释放增加此外，我们预测衰老的 γ δ T 细胞表现出偏向于炎症的功能特征。在此应用中，我们研究了对直接 HIV 感染和/或刺激因素的细胞因子/细胞毒性。建议使用先进和创新的方法来测试这些假设，包括 25 色流式细胞术，直肠乙状结肠活检的 31 色成像质谱流式分析、血浆和细胞培养物的 19 重和 33 重分析分别是上清液，以及对收集的数据集进行多变量分析的多种算法。生物信息数据分析计划将能够识别新的 γ δ T 细胞亚群并解析差异影响在目标 1 中，我们将对 HIV 与衰老进行横断面研究。队列确定循环γδT细胞亚群、血浆炎症和肠道之间的联系在目标 2 中，我们将确定通透性标记物、肠道结构和细胞组成。 γδT 细胞亚群、血浆标志物与老年病的发病和/或进展之间的时间联系在目标 3 中，我们将通过对患有和未患有 ART 抑制的艾滋病毒的老年受试者进行纵向研究来了解结果。进行体外测定以确定年龄和 HIV 感染如何影响 γ δ T 细胞功能，包括容量我们预测我们提出的实验将鉴定出肠上皮细胞单层。导致全身炎症和年龄相关合并症增加的生物机制无病毒血症的艾滋病病毒感染者和一般老年人群；这种认识可能会导致以下情况的发展：减少“炎症衰老”相关疾病和死亡的新疗法。