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Antibody Responses in HIV and Aging

HIV 和衰老中的抗体反应

基本信息

批准号：
9283348
负责人：
Savita Pahwa
金额：
$ 53.84万
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 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9283348
关键词：
AIDS/HIV problem Adult Adverse effects Affinity Age Aging Alpha Cell Anti-Inflammatory Agents Anti-inflammatory Antibodies Antibody Formation Antibody Response Antibody titer measurement Antigens B cell differentiation B-Lymphocyte Subsets B-Lymphocytes Biological Markers Blood specimen CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cardiovascular Diseases Cell physiology Cells 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 System and Related Disorders Immune response Immune system Immunoglobulin Somatic Hypermutation Immunoglobulin-Secreting Cells Immunologics Impairment Incidence Inflammaging Inflammation Inflammatory Influenza Influenza A Virus, H1N1 Subtype Influenza vaccination Interleukin-10 Interleukin-6 Life Expectancy Malignant Neoplasms Mediating Memory Menopause MicroRNAs Molecular Profiling Nature Neurocognitive Deficit Organ Participant Patients Peripheral Persons Phenotype Physiological Pilot Projects Plant Roots Plasma Population Population Control Population Group Property Research Risk Role Serum Stroke Structure of germinal center of lymph node T-Lymphocyte TNF gene Ursidae Family Vaccination Vaccines Viral Viremia Woman activation-induced cytidine deaminase age effect aged antiretroviral therapy base burden of illness cohort cytokine differentiated B cell immune activation immune function immunological status improved influenza virus vaccine insight macrophage microbial monocyte novel pathogen peripheral blood prevent public health relevance response seasonal influenza senescence study population tool vaccine response 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，美国大约一半的艾滋病毒感染者年龄将超过 50 岁。但艾滋病毒感染者的中位预期寿命仍然落后于未感染艾滋病毒者约 10 年。 HIV 感染和衰老的共同点是促炎症状态增加和免疫功能受损，并且对流感疫苗的抗体 (Ab) 反应明显缺陷。 HIV 是否会加速衰老或对衰老的不利影响具有累加效应尚不清楚，但 HIV 感染的存在会大大增加“炎症”、免疫衰老，并增加患终末器官疾病（称为 HIV 相关非艾滋病 (HANA) 疾病）的风险，这些疾病发生的年龄比未感染者更年轻。该应用程序基于我们对三个队列的试点观察。首先，与未感染的更年期女性相比，接受联合抗逆转录病毒治疗 (cART) 的病毒抑制的更年期 HIV 感染女性表现出更高的炎症细胞因子谱、肠道微生物易位 (MT) 以及 CD4 T 细胞、CD8 T 细胞和巨噬细胞的细胞免疫激活；重要的是，免疫激活状态与流感抗体反应呈负相关。其次，在对流感疫苗反应较差的年轻 HIV 感染患者群体中，我们发现了一种新型外周 CD4 辅助细胞亚群的功能潜在缺陷，该亚群被称为滤泡辅助 T 细胞 (pTfh)，其功能与生发中心 Tfh (GC Tfh) 细胞相似，而生发中心 Tfh (GC Tfh) 细胞是 B 细胞分化为抗体分泌细胞的主要驱动因素。第三，在 HIV 阴性老年人中，B 细胞内在 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佳。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/免疫激活会对生理衰老和艾滋病毒疾病中流感疫苗的免疫反应产生负面影响，并且这种影响在老龄化艾滋病毒感染人群中更为复杂。我们将对年龄层为 18-40、41-60 和 >60 岁的接受 cART 病毒学抑制的 HIV 感染患者（以及对照 HIV 未感染人群）进行拟议的研究，并收集疫苗接种前、疫苗接种后 7 天、3-4 周和 6 个月的外周血样本。我们的具体目标是： 1. 研究免疫激活对季节性流感疫苗接种抗体反应影响的性质和机制； 2. 表征外周滤泡辅助T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. 表征 B 细胞、T 独立反应以及免疫激活对其功能的作用。了解这些问题对于 HIV 阳性老年人改进疫苗和预防疫苗可预防的感染并发症至关重要。