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.

抽象的即使成功地控制病毒，HIV感染的个体也会表现出与老年相关的合并症，包括骨质疏松症，中风，痴呆和癌症。在无毒HIV+个体和一般老年人口，与年龄相关的疾病和死亡率与炎症和肠道的血浆标记相关渗透性。该肠道是潜在的HIV感染细胞的主要储藏室和HIV肠病，被定义为小肠和结肠中的病理过程是艾滋病毒感染的标志。我们的初步数据在ART抑制的HIV感染中，实施伽马三角细胞作为炎症驱动器，并且正常老化。伽马三角T细胞是一种规定的T细胞谱系，完成了≤10％的循环T细胞的≤10％，但在肠上皮的比例要高得多。另外，有证据表明这个独特的T细胞人口调节正常条件下的肠道屏障功能，伽玛d促促炎性活性在上皮部位和上皮屏障会造成损害。因此，我们实际上假设抑制HIV感染并随着正常衰老，胃肠道伽马D型T细胞通过直接燃烧而刺激艾滋病毒和/或暴露于炎症因素，这种异常激活导致紧密连接的崩溃肠上皮屏障，导致微生物产物的释放增加，炎症性伽马三角细胞释放到循环。此外，我们预测，老化的伽马三角T细胞暴露于偏向炎症的功能曲线响应直接HIV感染和/或刺激因素的细胞因子/细胞毒性。在此应用程序中，我们提出使用高级和创新方法测试这些假设的建议，包括25色流式细胞术， 31色成像对直径 - sigmoid活检，血浆和细胞培养的19-和33个质量分析的质量细胞仪分别用于收集数据集的多元分析的上清液和多个算法。我们的生物信息学数据分析计划将使识别新颖的伽马三角细胞子集并解析差异影响患有和没有HIV感染的年龄。在AIM 1中，我们将对艾滋病毒和衰老进行横断面研究队列以确定循环伽马三角细胞亚群，血浆炎症和肠之间的联系渗透性标记，肠结构和细胞组成。在AIM 2中，我们将确定伽马三角细胞子集，等离子体标记与老年病的发作和/或进展之间的临时联系通过对有或没有艺术抑制艾滋病毒的老年受试者进行的纵向研究，结果。在AIM 3中，我们将进行体外测定，以确定年龄和艾滋病毒感染如何影响伽马三角细胞功能，包括能力分解肠上皮细胞单层。我们预测我们提出的实验将确定驱动增加全身性炎症和年龄相关的合并症的生物学机制艾滋病毒+个体和一般老年人群；这种见解可能导致减少“炎症”相关疾病和死亡的新型疗法。