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

由于艾滋病毒感染者的年龄增大和心血管疾病(CVD)风险高 据预测，到2030年，78%的艾滋病毒携带者将被诊断为心血管疾病。 在女性机构间艾滋病毒研究(WIHS)的参与者中，我们建议研究一种 将从一项仅针对女性的研究扩展到包括男性的广泛特征的队列 合并和不合并临床和亚临床脑血管病。我们提出以下具体目标：1.以人为本 艾滋病毒携带者，以解决特定的先天性和获得性免疫细胞 子集将显示与心血管疾病相关的明确的转录改变。我们发现， HIV和CVD都能在经典单核细胞中产生致炎基因表达特征 这部分重叠了。然而，人类血液(PBMC)至少包含30个已知的亚群 免疫细胞类型，只有现在才能用PBMCs的Ab-Seq和scRNA-Seq来查询。 初步数据证明了该方法的可行性。2.鉴定相关基因的表达 组织因子(TF)和其他凝血相关途径与艾滋病毒，心血管疾病， 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 动脉粥样硬化抗原载脂蛋白B(APOB)特异性失去其调节性T细胞 (Treg)表型，并了解其促进CVD的机制。 艾滋病毒携带者。一个重要的工具是我们用来寻找稀有物质的有效四聚体试剂 表达主要致病基因DRB1*0701的受试者ApoB特异的CD4T细胞 组织相容性复合体(MHC)-II，约占所有受试者的8%。我们确认了69个 DRB1*0701阳性WIHS参与者。APOB特定的单元将按以下方式分类到单井中 DRB1*0701-APOB-P18四聚体。用SMART-Seq2对scRNA-Seq和Ab-Seq进行深度处理将产生 动脉粥样硬化特异性CD4的第一个T细胞受体(TCR)序列和匹配的转录本 T细胞。拟议的工作有可能发现现有或可寻址的新目标 新药，这可能会改善艾滋病毒携带者的心血管结果。该项目将 利用20多年的WIHS样本和数据归档、新参与者登记和CVD 由NHLBI未来承诺承保主要艾滋病毒队列实现的事件收集 基础设施支撑。

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.