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

据估计，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老龄化与年龄相关的免疫反应的变化和艾滋病毒感染的影响有关。 慢性HIV感染的免疫后果。艾滋病毒和衰老的交叉点将影响宿主 对感染的防御和对疫苗的反应。因此，了解与艾滋病毒相关的 免疫激活和免疫衰老具有特别的紧迫性。我们将利用我们的 已发表和正在进行的关于衰老对先天免疫模式识别失调的影响的研究 受体（PRR）功能，促炎性IL-7受体低效应记忆（EM）CD 8 T 在HIV阴性的老年人中扩增的细胞，以及在HIV阳性的老年人中扩增的EM CD 8 T细胞 成年人了我们还阐明了流感疫苗应答的基因表达和免疫学特征 在年轻和年长的HIV阴性成年人中。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，特别是在流感疫苗接种后。解决 为了解决这些问题，我们组建了一个跨学科的研究小组， 人类先天和适应性免疫系统的老化，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和抑制炎症反应的环境， HIV感染增强了HIV感染老年人的免疫衰老。为了验证这个假设，我们将 招募接受高剂量流感的年轻（21-35岁）和老年（65岁以上）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细胞计数， 评估主要群体（例如单核细胞，树突细胞，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。我们将评估先天的 免疫PRR功能（包括Toll样和NOD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， 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受体和EM CD 8 T细胞亚群。统计建模将包括临床和功能 协变量（例如，CD 4 + T细胞计数、HIV疾病和ART的估计持续时间、医学共病， 药物使用、功能状态）。最后，我们将获得流感疫苗的基因表达特征 在年轻和老年艾滋病毒感染者中的反应，并将这些与我们以前在 艾滋病毒阴性的成年人。我们将采用最先进的分析方法来整合基因表达， 免疫学数据，以全面了解年龄背景下的人体免疫应答， 免疫抑制这些研究最终旨在确定适合药理学的途径。 目标是改善患有艾滋病毒疾病的老年人（和年轻人）的免疫和疫苗反应。

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.