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在50岁以上。 艾滋病毒感染人群的老龄化将与年龄相关的免疫反应的变化与 慢性艾滋病毒感染的免疫学后果。艾滋病毒和老龄化的交集将影响宿主 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显得尤为紧迫。我们将利用来自我们的 已发表和正在进行的关于衰老对调节失调的天然免疫模式识别的影响的研究 受体(PRR)功能--一种新的促炎性IL-7受体低效应记忆(EM)CD8T细胞 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EM CD8 T细胞的扩增 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。 在年轻和年长的艾滋病毒阴性成年人中。这些发现使我们能够阐明衰老和艾滋病毒的影响。 感染对先天和适应性免疫功能的影响，特别是在接种流感疫苗后。致信地址 为了解决这些问题，我们召集了一个跨学科的调查小组，他们在研究 人类先天免疫系统和适应性免疫系统的老化，以及艾滋病毒免疫学、生物学和临床护理。 我们的主要假设是，促炎环境与年龄和受抑制的 艾滋病毒感染增强了患有艾滋病毒的老年人的免疫衰老。为了检验这一假设，我们将 招募年轻(21-35岁)和老年(65岁以上)感染艾滋病毒并接受大剂量流感治疗的成年人 疫苗。我们将使用最先进的方法，包括对全血进行多通道质量细胞分析，以 评估主要群体(如单核细胞、树突状细胞、自然杀伤细胞、 淋巴细胞、中性粒细胞)，包括疫苗前和疫苗后对血小板的新研究。我们将对先天进行评估 免疫PRR功能(包括Toll样受体家族成员和NOD样受体家族成员)，我们之前在那里发现 与增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受体低EM CD8 T细胞亚群。统计建模将包括临床模型和功能模型 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、 用药情况、功能状态)。最后，我们将得到流感疫苗的基因表达特征 年轻人和老年人对HIV疾病的反应，并将这些与我们之前在 HIV阴性的成年人。我们将使用最先进的分析方法来整合基因表达和 免疫学数据，以获得在年龄和环境中人类免疫反应的全面看法 免疫抑制。这些研究的最终目的是确定符合药理作用的途径。 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。

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.