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: 10217237
• 负责人: Robert C Kaplan
• 金额: $ 81.41万
• 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/10217237
• 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.

由于年龄的增长和心血管疾病（CVD）的高风险HIV感染者