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: 9803224
• 负责人: Robert C Kaplan
• 金额: $ 84.66万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9803224
• 关键词: Address; Alleles; Antibodies; Antigens; Apolipoproteins B; Archives; 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; Enrollment; 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; Specimen; Surface; System; T-Cell Receptor; Testing; Thromboplastin; Travel; Triad Acrylic Resin; Vascular Diseases; Woman; Women’s Interagency HIV Study; Work; base; 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; phenotypic data; precision medicine; programs; response; single cell sequencing; single-cell RNA sequencing; stroke event; 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.

由于艾滋病毒感染者的年龄增长和心血管疾病（CVD）的高风险， 据预测，到2030年，78%的艾滋病毒感染者将被诊断为CVD。 在妇女机构间艾滋病毒研究（WIHS）的参与者中，我们建议研究一个 将从仅女性研究扩展至包括男性的广泛特征队列 有或没有临床和亚临床CVD。我们提出这些具体目标：1。人口 艾滋病毒感染者，以解决特定的先天性和适应性免疫细胞 子集将显示与CVD相关的确定的转录组学变化。我们发现 HIV和CVD都在经典单核细胞中产生促炎基因表达标记 部分重叠。然而，人血液（PBMC）含有至少30种已知的免疫调节剂亚群。 免疫细胞类型，其仅现在可以使用PBMC的Ab-Seq和scRNA-Seq来询问。 初步数据证明了可行性。2.为了鉴定与以下相关的基因的表达： 组织因子（TF）和其他与HIV，CVD， 炎症、血脂异常和他汀类药物的使用。3.为了验证CD 4 + T细胞 特异性针对动脉粥样硬化抗原载脂蛋白B（APOB）的调节性T细胞 （Treg）表型，并了解其促进CVD的机制。 艾滋病毒感染者。一个关键的工具是经过验证的四聚体试剂， 表达DRB 1 *0701等位基因的受试者中的APOB特异性CD 4 T细胞 组织相容性复合体（MHC）-II的受试者占所有受试者的约8%。我们发现69个 DRB 1 *0701阳性WIHS参与者。将载脂蛋白B特异性细胞分选至单个威尔斯孔中， DRB 1 *0701-APOB-p18四聚体。通过SMART-Seq 2进行的深度scRNA-Seq和Ab-Seq将产生 动脉粥样硬化特异性CD 4的第一T细胞受体（TCR）序列和匹配的转录组 T细胞。拟议的工作有可能发现新的目标， 新的药物，这可能会改善艾滋病毒感染者的心血管结局。该项目将 利用20多年的WIHS标本和数据档案、新参与者招募和CVD 通过NHLBI未来承诺承保主要HIV队列，实现事件收集 基础设施支持。