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.

由于艾滋病毒感染者的年龄增长和心血管疾病（CVD）风险较高 据预测，到 2030 年，78% 的艾滋病毒感染者将被诊断出患有心血管疾病。 在妇女机构间艾滋病毒研究 (WIHS) 的参与者中，我们建议研究一项 一般特征队​​列将从仅限女性的研究扩展到包括男性 我们提出以下具体目标： 1. 在人中。 感染艾滋病毒，以解决特定先天性和适应性免疫细胞的假设 我们发现，子集将显示与 CVD 相关的明确转录组变化。 HIV 和 CVD 都会在经典单核细胞中产生促炎基因表达特征 然而，人类血液 (PBMC) 至少包含 30 个已知的子集。 免疫细胞类型，目前只能使用 PBMC 的 Ab-Seq 和 scRNA-Seq 进行检测。 初步数据证明了有效性 2. 鉴定相关基因的表达。 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. 检验 CD4+ T 细胞的假设。 特异性针对动脉粥样硬化抗原载脂蛋白 B (APOB) 失去调节性 T 细胞 (Treg) 表型并了解其促进 CVD 的机制 艾滋病毒感染者的一个重要工具是经过验证的四聚体试剂，我们用它来寻找罕见的病毒。 表达主要 DRB1*0701 等位基因的参与者中的 APOB 特异性 CD4 T 细胞 组织相容性复合体 (MHC)-II，约占所有受试者的 8% 我们鉴定了 69 名受试者。 DRB1*0701 阳性 WIHS 参与者将被分选到单孔中。 DRB1*0701-APOB-p18 四聚体通过 SMART-Seq2 进行深度 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 的匹配转录组 拟议的工作有可能发现现有或可寻址的新靶点。 新的，这可能会改善艾滋病毒感染者的心血管结果。 利用 20 多年的 WIHS 样本和数据档案、新参与者注册和 CVD NHLBI 未来承诺承保主要 HIV 队列，从而实现事件收集 基础设施支持。