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，美国大约一半的艾滋病毒感染者年龄超过 50 岁。 HIV感染者的老龄化与年龄和免疫力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叉将影响宿主 防御感染和对疫苗的反应。因此，了解艾滋病毒相关的关系 免疫激活和免疫衰老显得尤为紧迫。我们将利用我们的见解 关于衰老对先天免疫模式识别失调的影响已发表和正在进行的研究 受体 (PRR) 功能，一种新型促炎性 IL-7 受体，可降低效应记忆 (EM) CD8 T 细胞在 HIV 阴性老年人中扩增，以及 EM CD8 T 细胞在老年 HIV 阳性者中扩增 成年人。我们还阐明了流感疫苗反应的基因表达和免疫学特征 年轻和年长的艾滋病毒阴性成年人。这些发现使我们能够阐明衰老和艾滋病毒的影响 感染对先天性和适应性免疫功能的影响，特别是在接种流感疫苗后。致地址 为了解决这些问题，我们组建了一个跨学科研究小组，由具有研究专业知识的研究人员组成 人类先天和适应性免疫系统的衰老，以及艾滋病毒免疫学、生物学和临床护理。 我们的首要假设是，促炎环境与年龄和抑制相关 HIV 感染会增强患有 HIV 疾病的老年人的免疫衰老。为了检验这个假设，我们将 招募年轻（21-35 岁）和老年人（65 岁以上）接受高剂量流感的 HIV 感染者 疫苗。我们将采用最先进的方法，包括对全血进行多通道质谱流式细胞术 评估主要细胞群（例如单核细胞、树突状细胞、NK 细胞、 淋巴细胞、中性粒细胞），包括疫苗接种前和接种后血小板的新研究。我们将评估先天 免疫PRR功能（包括Toll样和NOD样受体家族成员），我们之前发现 与年龄相关的细胞因子产生和共刺激蛋白表达的变化与 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 alow EM CD8 T 细胞亚群。统计模型将包括临床和功能 协变量（例如 CD4+ T 细胞计数、HIV 疾病和 ART 的估计持续时间、医疗合并症、 药物使用、功能状态）。最后，我们将得出流感疫苗的基因表达特征 患有艾滋病毒的年轻人和老年人的反应，并将这些反应与我们之前在 HIV 阴性成年人。我们将采用最先进的分析方法来整合基因表达和 免疫学数据，以全面了解年龄和年龄背景下的人体免疫反应 免疫抑制。这些研究的最终目的是确定适合药理学的途径 旨在改善患有艾滋病毒的老年人（和年轻人）的免疫和疫苗反应。