Determinants of Functional Immune Defects in Treated HIV Infection and Aging

产品说明：尽管有最佳的抗逆转录病毒治疗（ART），艾滋病毒感染者的死亡率和几个与衰老相关的发病率比一般人群继续增加的风险。治疗的HIV感染的慢性炎症状态似乎预测了许多这些发病率，并且也被认为导致过早的“免疫衰老”，功能性T细胞缺陷通常见于年龄大得多的HIV未感染个体。然而，在治疗的HIV感染中损害功能性免疫反应的特定T细胞缺陷是未知的，并且可能与在衰老中观察到的那些完全不同。来自我们小组的初步数据表明，在HIV感染个体中，增殖史标志物CD 57在效应CD 28-CD 8 + T细胞上异常低，在抑制性ART期间增加，但未能正常化。ART期间这种持续低的CD 57缺陷与单核细胞活化和吲哚胺2，3-双加氧酶（IDO）诱导（增殖性T细胞缺陷的已知驱动因素）相关，并强烈预测这种情况下死亡率增加。这些CD 8 + T细胞缺陷与衰老相关的免疫衰老非常不同，后者的典型特征是效应CD 8 + T细胞上的CD 57增加。这些数据激发了这样的假设，即在治疗的HIV疾病中负责功能性适应性免疫缺陷的表型T细胞缺陷与在老年HIV感染者中观察到的那些完全不同。我们将在一个由200名HIV感染者和100名未感染者组成的队列中直接讨论这一假设，具体目标如下：1）确定维持ART介导的病毒抑制的HIV感染个体是否比年龄匹配的HIV未感染个体具有更差的疫苗应答性，以及这些缺陷是否可以通过早期开始ART逆转，2）表征在治疗的HIV感染和衰老中预测疫苗应答性差的表型T细胞缺陷，和3）表征先天免疫激活途径与治疗的HIV感染和衰老中疫苗应答性差之间的关系。通过表征在治疗的HIV感染中疫苗反应性受损的免疫决定因素以及它们与衰老相关的免疫衰老的免疫决定因素的不同，该项目将有助于确定新干预措施的目标，以恢复HIV感染者的免疫功能和健康。

DESCRIPTION: Despite optimal antiretroviral therapy (ART), HIV-infected individuals continue to have an increased risk of mortality and several aging-associated morbidities than the general population. The chronic inflammatory state of treated HIV infection appears to predict many of these morbidities and is also thought to lead to premature "immunosenescence," functional T cell defects typically seen in much older HIV-uninfected individuals. However, the specific T cell defects that impair functional immune responses in treated HIV infection are unknown and may be quite distinct from those observed in aging. Preliminary data from our group suggests that the proliferative history marker CD57 is abnormally low on effector CD28- CD8+ T cells in HIV-infected individuals, increases during suppressive ART, but fails to normalize. This persistently low CD57 defect during ART is associated with monocyte activation and indoleamine 2,3-dioxygenase (IDO) induction, known drivers of proliferative T cell defects, and strongly predicts increased mortality in this setting. These CD8+ T cell defects are quite distinct from aging-associated immunosenescence, which is typically characterized by increased CD57 on effector CD8+ T cells. These data motivated the hypothesis that the phenotypic T cell defects responsible for functional adaptive immune defects in treated HIV disease are quite distinct from those observed in elderly HIV-infected individuals. We will address this hypothesis directly in a cohort of 200 HIV-infected and 100 HIV-uninfected individuals with the following specific aims: 1) To determine whether HIV-infected individuals maintaining ART-mediated viral suppression have poorer vaccine responsiveness than age-matched HIV-uninfected individuals and whether these defects can be reversed by early initiation of ART, 2) to characterize the phenotypic T cell defects that predict poor vaccine responsiveness in both treated HIV infection and aging, and 3) to characterize the relationship between innate immune activation pathways and poor vaccine responsiveness in treated HIV infection and aging. By characterizing the immunologic determinants of impaired vaccine responsiveness in treated HIV infection and how they may differ from those of aging-associated immunosenescence, this project will help identify targets for novel interventions to restore immune function and health in HIV-infected individuals.