The Impact of Aging and HIV Infection on Immunologic and Transcriptomic Signatures of Influenza Vaccine Response

衰老和 HIV 感染对流感疫苗反应的免疫学和转录组学特征的影响

• 批准号: 10183118
• 负责人: Insoo Kang
• 金额: $ 77.91万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10183118
• 关键词: 20 year old; 21 year old; Address; Adult; Affect; Age; Age-Years; Aging; Antibodies; B-Lymphocyte Subsets; B-Lymphocytes; Biological; Biology; Blood Platelets; Blood specimen; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Count; Characteristics; Chronic; Chronic Disease; Chronic Obstructive Airway Disease; Clinical; Coronary Arteriosclerosis; Cytometry; Data; Defect; Dendritic Cells; Development; Diabetes Mellitus; Disease; Dose; Elderly; Enrollment; Equation; Family member; Flow Cytometry; Gap Junctions; Gene Expression; Gene Expression Profile; HIV; HIV Infections; HIV Seronegativity; HIV Seropositivity; HIV-1; Head; Host Defense; Human; Immune; Immune response; Immune system; Immunity; Immunoglobulin G; Immunologics; Immunology; Immunosuppression; Impairment; In Vitro; Individual; Infection; Inflammatory; Influenza; Influenza Hemagglutinin; Influenza vaccination; Interleukin 7 Receptor; Life Expectancy; Link; Lymphocyte; Medical; Memory; Methods; Modeling; Natural Killer Cells; Outcome; Pathway Analysis; Pathway interactions; Pattern; Pattern recognition receptor; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacology; Phenotype; Physical Performance; Population; Positioning Attribute; Production; Publishing; Research Personnel; Risk Factors; Statistical Models; Structure; System; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic Intervention; Toll-like receptors; United States; Vaccination; Vaccine Antigen; Vaccines; Whole Blood; age effect; analytical method; antiretroviral therapy; cell type; clinical care; comorbidity; cytokine; functional status; human old age (65+); immune activation; immune function; immune system function; immunosenescence; improved; inflammatory milieu; influenza virus vaccine; innate immune function; insight; monocyte; neutrophil; novel; protein expression; receptor; receptor function; recruit; responders and non-responders; response; stem; supervised learning; therapy development; transcriptome sequencing; transcriptomics; vaccine response; young adult

It is estimated that approximately half of HIV-infected individuals in the United States are over 50 years of age. Aging of the HIV-infected population has linked alterations in immune responses associated with age and the immunologic consequences of chronic HIV infection. This intersection of HIV and aging will influence host defense against infection and response to vaccines. As a result, understanding the nexus of HIV-associated immune activation and immunosenescence takes on particular urgency. We will leverage insights from our published and ongoing studies on the effects of aging on dysregulated innate immune pattern recognition receptor (PRR) function, a novel population of pro-inflammatory IL-7 receptor alow effector memory (EM) CD8 T cells that are expanded in HIV-negative older adults, and on expansion of EM CD8 T cells in older HIV-positive adults. We have also elucidated gene expression and immunologic signatures of influenza vaccine response in young and older HIV-negative adults. These findings position us to illuminate the effects of aging and HIV infection on innate and adaptive immune function, particularly following influenza vaccination. To address these questions, we have assembled an interdisciplinary group of investigators with expertise in the study of aging of the innate and adaptive human immune systems, and in HIV immunology, biology and clinical care. Our overarching hypothesis is that the pro-inflammatory environment associated with age and with suppressed HIV infection potentiates immunosenescence in older adults with HIV disease. To test this hypothesis, we will enroll young (age 21-35) and older (age over 65) adults with HIV infection receiving high-dose influenza vaccine. We will employ state of the art methods including multichannel mass cytometry on whole blood to assess development and activation of major populations (e.g. monocytes, dendritic cells, NK cells, lymphocytes, neutrophils), including novel studies of platelets pre- and post-vaccine. We will evaluate innate immune PRR function (including Toll-like and NOD-like receptor family members), where we previously found age-associated alterations in cytokine production and costimulatory protein expression that were related to influenza vaccine response. We will also study T cell responses to in vitro vaccine antigen stimulation, including the IL-7 receptor alow EM CD8 T cell subset. Statistical modeling will include clinical and functional covariates (e.g. CD4+ T cell count, estimated duration of HIV disease and of ART, medical co-morbidities, medication use, functional status). Finally, we will derive gene expression signatures of influenza vaccine response in young and older adults with HIV disease, and compare these to those we previously identified in HIV-negative adults. We will employ state of the art analytic methods to integrate gene expression and immunologic data to obtain a comprehensive view of the human immune response in the context of age and immune suppression. These studies ultimately are aimed at identifying pathways amenable to pharmacologic targeting to improve immune and vaccine responses in older (and young) adults with HIV disease.

据估计，在美国，大约一半的艾滋病毒感染者年龄超过50岁。 艾滋病毒感染人群的衰老与年龄和年龄相关的免疫反应的改变有关 慢性艾滋病毒感染的免疫学后果。艾滋病毒和衰老的这种交集将影响宿主 防御感染和对疫苗的反应。结果，了解与HIV相关的联系 免疫激活和免疫衰老具有特殊的紧迫性。我们将利用我们的见解 关于衰老对失调的先天免疫模式识别的影响和正在进行的研究 受体（PRR）功能，促炎性IL-7受体效应器记忆（EM）CD8 T的新型人群 在HIV阴性老年人中膨胀的细胞，以及在较老HIV阳性的EM CD8 T细胞扩张后 成年人。我们还阐明了流感疫苗反应的基因表达和免疫信号 在年轻和年龄较大的HIV阴性成年人中。这些发现的定位是我们照亮衰老和艾滋病毒的影响 对先天和适应性免疫功能的感染，尤其是流感疫苗接种后。解决 这些问题，我们组建了一个跨学科研究人员，具体知识 先天和适应性人类免疫系统的老化，以及HIV免疫学，生物学和临床护理。 我们的总体假设是与年龄相关的促炎环境 HIV感染增强了HIV疾病老年人的免疫衰老。为了检验这一假设，我们将 注册年轻人（21-35岁）和年龄较大（65岁以上）患有艾滋病毒感染的成年人接受高剂量流感 疫苗。我们将采用艺术方法的状态方法，包括全血的多通道质量细胞仪到 评估主要人群的开发和激活（例如单核细胞，树突细胞，NK细胞， 淋巴细胞，嗜中性粒细胞），包括对疫苗前后血小板的新研究。我们将评估先天 免疫PRR功能（包括Toll样和点头样受体家族成员），我们以前发现 与年龄相关的细胞因子产生和共刺激蛋白表达的改变与 流感疫苗反应。我们还将研究T细胞对体外疫苗抗原刺激的反应， 包括IL-7受体EM CD8 T细胞子集。统计建模将包括临床和功能 协变量（例如CD4+ T细胞计数，HIV疾病和ART的估计持续时间，医学合并症， 用药使用，功能状态）。最后，我们将得出流感疫苗的基因表达特征 在患有艾滋病毒疾病的年轻人和老年人中的反应，并将其与我们先前在 HIV阴性成年人。我们将采用艺术分析方法来整合基因表达和 免疫数据以在年龄和 免疫抑制。这些研究最终旨在确定适合药理的途径 靶向改善艾滋病毒疾病的老年人（和年轻）成年人的免疫和疫苗反应。