Antibody Responses in HIV and Aging

HIV 和衰老中的抗体反应

基本信息

批准号：
8604099
负责人：
Savita Pahwa
金额：
$ 52.92万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8604099
关键词：
AIDS/HIV problem Adult Adverse effects Affinity Age Aging Anti-Inflammatory Agents Anti-inflammatory Antibodies Antibody Formation Antigens B cell differentiation B-Lymphocyte Subsets B-Lymphocytes Biological Markers Blood specimen CD4 Positive T Lymphocytes CD8B1 gene Cardiovascular Diseases Cell physiology Cells Cellular translocation Characteristics Defect Development Diabetes Mellitus Disease Elderly Enrollment Exhibits Failure Fire - disasters Frequencies Goals HIV HIV Infections Hand Helper-Inducer T-Lymphocyte IL8 gene Immune Immune System Diseases Immune response Immune system Immunoglobulin Somatic Hypermutation Immunoglobulin-Secreting Cells Immunologics Incidence Inflammation Inflammatory Influenza Influenza A Virus, H1N1 Subtype Influenza vaccination Interleukin-10 Interleukin-6 Life Life Expectancy Malignant Neoplasms Mediating Memory Menopause MicroRNAs Molecular Profiling Nature Neurocognitive Organ Participant Patients Peripheral Persons Physiological Pilot Projects Plant Roots Plasma Population Population Group Population Study Property Research Risk Role Serum Stroke Structure of germinal center of lymph node T-Lymphocyte TNF gene Tumor Necrosis Factor-alpha Ursidae Family Vaccination Vaccines Viremia Woman activation-induced cytidine deaminase age effect aged antiretroviral therapy base burden of illness cohort cytokine human TNF protein humoral immunity deficiency immune activation immune function improved influenza virus vaccine insight macrophage microbial monocyte novel pathogen peripheral blood prevent public health relevance response seasonal influenza senescence tool volunteer

项目摘要

DESCRIPTION: By 2015, approximately half of people living with HIV in the US will be >50 yr. of age but median life expectancy of HIV infected persons continues to lag behind that of HIV uninfected by approximately 10 years. What HIV infection and aging have in common is increased pro-inflammatory state and compromised immune function with demonstrable deficits in antibody (Ab) responses to influenza vaccines. Whether HIV accelerates aging or has additive effect on adverse effects of aging is unclear, but presence of HIV infection greatly increases "inflammaging", immune senescence and increased risk of end-organ disorders termed HIV-associated non-AIDS (HANA) conditions that occur at younger ages than uninfected persons. This application is based on our pilot observations in three cohorts. First, virally suppressed menopausal HIV- infected women on combination antiretroviral therapy (cART) exhibited higher inflammatory cytokine profile, gut microbial translocation (MT) and cellular immune activation of CD4 T cells, CD8 T cells and macrophages in comparison to uninfected menopausal women; importantly, the immune activation status was negatively associated with influenza Ab response. Second, in a younger cohort of HIV infected patients with poor responses to influenza vaccines we identified a potential defect in the function of a novel peripheral CD4 helper subset designated as T follicular helper cell (pTfh) that bears functional resemblance to the germinal center Tfh (GC Tfh) cells, which are prime drivers of B cell differentiation into antibody secreting cells. Third, in HIV negative aged adults, B cell intrinsic TNF-alpha and higher microRNA-155 were predictive of B cell functional defects and poor antibody response to influenza vaccine. These observations underscore the implications of the inflammation/immune activation on immune dysfunction. We hypothesize that inflammation/immune activation negatively impacts the immune response to influenza vaccines in physiologic aging and in HIV disease, and the effect is compounded in the aging HIV infected population. We will conduct the proposed studies in virologicallly suppressed HIV infected patients on cART (and control HIV uninfected populations) in age strata 18- 40, 41-60, and >60 years with peripheral blood samples collected pre-vaccination, at 7 days, at 3-4 weeks and 6 month post-vaccination. Our specific aims are: 1. To investigate the nature and mechanism of the effect of immune activation on Ab responses to seasonal flu vaccination; 2. To characterize the function of peripheral T follicular helper cells in influenza antibody responses and role of immune activation on their function; and 3. To characterize B cells, T- independent responses and role of immune activation on their function. Understanding these issues is fundamentally important in the HIV+ elderly to improve vaccines and prevent vaccine preventable infectious complications.

描述：到2015年，大约一半在美国患艾滋病毒的人将> 50年。年龄，但受艾滋病毒感染者的预期寿命中位数继续落后于未感染大约10年的艾滋病毒。 HIV感染和衰老的共同点是增加促炎状态和免疫功能，具有对流感疫苗的抗体（AB）反应的明显缺陷。艾滋病毒是否会加速衰老或对衰老的不良影响产生累加作用，但艾滋病毒感染的存在大大增加了“炎症”，免疫衰老，并增加所谓的HIV相关非AID（HANA）疾病的最终器官疾病的风险，而年龄较小的年龄比单一患者发生。该应用程序基于我们在三个队列中的试点观察。首先，在抗逆转录病毒疗法（CART）中，病毒抑制的绝经HIV感染妇女（CART）表现出较高的炎性细胞因子特征，肠道微生物易位（MT）和CD4 T细胞，CD8 T细胞和巨噬细胞的细胞免疫激活与未感染的绝经女性相比；重要的是，免疫激活状态与流感AB反应负相关。 Second, in a younger cohort of HIV infected patients with poor responses to influenza vaccines we identified a potential defect in the function of a novel peripheral CD4 helper subset designated as T follicular helper cell (pTfh) that bears functional resemblance to the germinal center Tfh (GC Tfh) cells, which are prime drivers of B cell differentiation into antibody secreting cells.第三，在HIV阴性成年人中，B细胞固有 TNF-α和较高的microRNA-155可以预测B细胞功能缺陷和对流感疫苗的抗体反应不良。这些观察结果强调了炎症/免疫激活对免疫功能障碍的影响。我们假设炎症/免疫激活对生理衰老和HIV疾病中流感疫苗的免疫反应产生负面影响，并且在衰老的HIV感染人群中，这种影响更加复杂。我们将在18-40、41 - 60岁的年龄层（和对照HIV未感染的艾滋病毒未感染的人群中）对病毒学抑制的艾滋病毒感染患者进行拟议的研究，并在7天和6个月后6个月收集了7天，第7天，在7天和6个月中收集的周围血液样本，在7天和6个月内收集了60岁以上。我们的具体目的是：1。研究免疫激活对AB对季节性流感疫苗接种反应的影响的性质和机制； 2。表征外周T卵泡细胞在流感抗体反应中的功能以及免疫激活对其功能的作用； 3。为表征B细胞，T-独立反应和免疫激活对其功能的作用。了解这些问题在HIV+老年人中至关重要，以改善疫苗并防止疫苗可预防的感染并发症。