Antibody Responses in HIV and Aging

描述：到2015年，美国大约一半的艾滋病毒感染者将达到50岁，但艾滋病毒感染者的平均预期寿命继续落后于未感染艾滋病毒的人大约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有附加作用尚不清楚，但艾滋病毒感染的存在大大增加了“炎症”、免疫衰老和被称为艾滋病毒相关非艾滋病（HANA）疾病的终末器官疾病的风险，这些疾病发生在比未感染的人更年轻的年龄。该应用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）的病毒抑制的绝经期HIV感染妇女表现出更高的炎症细胞因子谱、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；重要的是，免疫激活状态与流感Ab反应呈负相关。其次，在对流感疫苗反应较差的年轻HIV感染患者队列中，我们发现了一种被称为T滤泡辅助细胞（pTfh）的新型外周CD4辅助亚群功能的潜在缺陷，该亚群与生发中心Tfh （GC Tfh）细胞具有功能相似性，后者是B细胞分化为抗体分泌细胞的主要驱动因素。第三，在HIV阴性的老年人中，B细胞固有

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.