Immunophenotyping for precision medicine for cardiovascular disease in people living with HIV

艾滋病毒感染者心血管疾病精准医学的免疫表型分析

• 批准号: 10453453
• 负责人: Robert C Kaplan
• 金额: $ 81.99万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453453
• 关键词: Address; Alleles; Antibodies; Antigens; Apolipoproteins B; Atherosclerosis; Attenuated; Blood; Blood Cells; Blood Chemical Analysis; Blood Coagulation Disorders; Blood specimen; CD4 Positive T Lymphocytes; CDK6-associated protein p18; Cardiovascular Diseases; Cardiovascular system; Carotid Arteries; Cell Surface Proteins; Cell surface; Cells; Chronic; Clinical; Coagulation Process; Cohort Studies; Collection; Complement; Cytometry; Data; Development; Diagnosis; Dyslipidemias; Elderly; Event; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Goals; HIV; Human; Immune; Immunophenotyping; Inflammation; Inflammatory; Infrastructure; Innate Immune Response; Leukocytes; Link; Lipoproteins; Major Histocompatibility Complex; Measures; Mediating; Medicine; Methodology; Methods; Modernization; Molecular; Myocardial Infarction; National Heart, Lung, and Blood Institute; Natural History; Outcome; Participant; Pathway interactions; Persons; Pharmaceutical Preparations; Phenotype; Population; Predisposing Factor; Reagent; Regulatory T-Lymphocyte; Sampling; Sorting - Cell Movement; Surface; System; T-Cell Receptor; Testing; Thromboplastin; Travel; Triad Acrylic Resin; Vascular Diseases; Woman; Women' s Interagency HIV Study; Work; base; biological specimen archives; cardiovascular disorder risk; cell type; clinical phenotype; cohort; drug development; evidence base; genome wide association study; immune activation; improved; innovation; intimal medial thickening; lipid disorder; longitudinal design; men; monocyte; novel therapeutics; participant enrollment; phenotypic data; precision medicine; programs; response; single cell sequencing; single-cell RNA sequencing; stroke event; systemic inflammatory response; technological innovation; tool; transcriptome; transcriptome sequencing; transcriptomics; whole genome

Due to the advancing age and high cardiovascular disease (CVD) risk of the HIV infected population, it is predicted that 78% of people living with HIV will be diagnosed with CVD by 2030. Among participants in the Women’s Interagency HIV Study (WIHS), we propose to study an extensively characterized cohort that will be extended from a women-only study to include men with and without clinical and subclinical CVD. We propose these specific aims: 1. In persons living with HIV, to address the hypothesis that specific innate and adaptive immune cell subsets will show defined transcriptomic changes associated with CVD. We have found that both HIV and CVD produce pro-inflammatory gene expression signatures in classical monocytes that partially overlap. However, human blood (PBMCs) contains at least 30 subsets of known immune cell types, which only now can be interrogated using Ab-Seq and scRNA-Seq of PBMCs. Preliminary data demonstrate feasibility. 2. To identify the expression of genes relating to tissue factor (TF) and other coagulation-related pathways in relation to HIV, CVD, inflammation, dyslipidemia and statin use. 3. To test the hypothesis that CD4+ T cells specific for the atherosclerosis antigen apolipoprotein B (APOB) lose their regulatory T cell (Treg) phenotype and to understand the mechanisms by which this promotes CVD in persons living with HIV. A critical tool is the validated tetramer reagent we use to find rare APOB-specific CD4 T cells in participants who express the DRB1*0701 allele of major histocompatibility complex (MHC)-II, comprising about 8% of all subjects. We identified 69 DRB1*0701 positive WIHS participants. The APOB-specific cells will be sorted into single wells by DRB1*0701-APOB-p18 tetramers. Deep scRNA-Seq and Ab-Seq by SMART-Seq2 will yield the first T cell receptor (TCR) sequences and matched transcriptomes for atherosclerosis-specific CD4 T cells. The proposed work has the potential to discover new targets addressable by existing or new drugs, which may improve cardiovascular outcomes in people with HIV. The project will leverage a 20+ year WIHS archive of specimens and data, new participant enrollment and CVD event collection enabled by a future commitment of NHLBI to underwrite the primary HIV cohort infrastructure support.

由于年龄的进步和高心血管疾病（CVD）感染了HIV的风险 人口，可以预测，艾滋病毒患者中有78％将于2030年被诊断出患有CVD。 在妇女间艾滋病毒研究（WIHS）的参与者中，我们建议研究 广泛特征的队列将从唯一的女性研究中扩展到包括男性 有和没有临床和亚临床CVD。我们提出了这些特定目标：1。 与艾滋病毒一起生活，以解决特定的先天和适应性免疫球的假设 子集将显示与CVD相关的定义的转录组变化。我们发现 HIV和CVD都在经典单核细胞中产生促炎基因表达特征 那部分重叠。但是，人类血液（PBMC）至少包含30个已知的子集 免疫细胞类型，直到现在才可以使用PBMC的AB-SEQ和SCRNA-SEQ进行询问。 初步数据证明了可行性。 2。确定与 组织因子（TF）和其他与HIV，CVD相关的凝结相关途径 炎症，血脂异常和他汀类药物的使用。 3。检验CD4+ T细胞的假设 针对动脉粥样硬化抗原载脂蛋白B（APOB）的特定调节性T细胞 （treg）表型并了解促进CVD的机制 患有艾滋病毒的人。一个关键的工具是我们使用的经过验证的四聚体试剂 表达drb1*0701主要等位基因的参与者的APOB特异性CD4 T细胞 组织相容性复合物（MHC）-II，约占所有受试者的8％。我们确定了69 DRB1*0701正wihs参与者。 APOB特异性单元将通过 DRB1*0701-APOB-P18四聚体。 smart-seq2的深scrna-seq和ab-seq将产生 第一个T细胞受体（TCR）序列和动脉粥样硬化特异性CD4的转录组 T细胞。拟议的工作有可能发现现有或 新药可以改善艾滋病毒患者的心血管结局。该项目将 利用20多年的标本和数据档案，新的参与者入学和CVD NHLBI未来承诺以承保主要艾滋病毒队列的事件收集 基础架构支持。