Antibody Responses in HIV and Aging

HIV 和衰老中的抗体反应

• 批准号: 9064747
• 负责人: Savita Pahwa
• 金额: $ 54.62万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 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/9064747
• 关键词: AIDS/HIV problem; Adult; Adverse effects; Affinity; Age; Aging; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antibody Formation; Antibody Response; 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; Health; 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 Deficit; Organ; Participant; Patients; Peripheral; Persons; Physiological; Pilot Projects; Plant Roots; Plasma; Population; Population Group; Property; Research; Risk; Role; Serum; Stroke; Structure of germinal center of lymph node; T-Lymphocyte; TNF gene; Ursidae Family; Vaccination; Vaccines; Viremia; Woman; activation-induced cytidine deaminase; age effect; aged; antiretroviral therapy; base; burden of illness; cohort; cytokine; humoral immunity deficiency; immune activation; immune function; improved; influenza virus vaccine; insight; macrophage; microbial; monocyte; novel; pathogen; peripheral blood; prevent; response; seasonal influenza; senescence; study population; tool; vaccine response; volunteer

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携带者将达到50岁。但是，艾滋病毒感染者的平均预期寿命仍然比未感染艾滋病毒的人晚约10年。HIV感染和衰老的共同之处是促炎状态增加和免疫功能受损，对流感疫苗的抗体(Ab)反应明显不足。艾滋病毒是否加速衰老或对衰老的不利影响具有相加作用尚不清楚，但艾滋病毒感染的存在极大地增加了“炎症”、免疫衰老和被称为艾滋病毒相关非艾滋病(HANA)的终末器官疾病的风险，这种疾病发生在比未感染的人更年轻的年龄。这一应用是基于我们在三个队列中的试点观察。首先，与未感染的绝经妇女相比，接受联合抗逆转录病毒治疗(CART)的绝经后HIV感染妇女表现出更高的炎性细胞因子谱、肠道微生物易位(MT)和细胞免疫激活的CD4T细胞、CD8T细胞和巨噬细胞；重要的是，免疫激活状态与流感抗体应答呈负相关。其次，在对流感疫苗反应不佳的HIV感染患者的年轻队列中，我们发现了一种新的外周CD4辅助细胞亚群潜在的功能缺陷，该亚群被称为T滤泡辅助细胞(PTfh)，其功能类似于生发中心Tfh(GC Tfh)细胞，后者是B细胞分化为抗体分泌细胞的主要驱动力。第三，在HIV阴性的老年人中，B细胞是固有的 肿瘤坏死因子-α和较高的microRNA-155是B细胞功能缺陷和对流感疫苗抗体反应差的预测指标。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，在生理性衰老和HIV疾病中，炎症/免疫激活对流感疫苗的免疫反应产生负面影响，并且在老龄化的HIV感染人群中，这种影响是复杂的。我们将在18-40岁、41-60岁和&gt；60岁的CART上对病毒学抑制的HIV感染患者(和对照HIV非感染人群)进行拟议的研究，并在接种前、接种后7天、接种后3-4周和6个月采集外周血样本。我们的具体目标是：1.研究免疫激活对季节性流感疫苗抗体应答的影响的性质和机制；2.研究外周血T滤泡辅助细胞在流感抗体应答中的作用以及免疫激活对其功能的影响；3.研究B细胞、T细胞非依赖性应答以及免疫激活对其功能的影响。了解这些问题对于艾滋病毒+老年人改进疫苗和预防疫苗可预防的传染病并发症至关重要。