Determinants of Functional Immune Defects in Treated HIV Infection and Aging

描述：尽管采用了最佳的抗逆转录病毒疗法(ART)，但与普通人群相比，HIV感染者的死亡率和几种与衰老相关的疾病的风险仍在增加。经过治疗的艾滋病毒感染的慢性炎症状态似乎可以预测其中许多疾病，也被认为会导致过早的“免疫衰老”，这是一种典型的功能性T细胞缺陷，通常见于年龄大得多的未感染艾滋病毒的人。然而，在接受治疗的HIV感染中损害功能性免疫反应的特定T细胞缺陷尚不清楚，可能与在衰老中观察到的完全不同。我们小组的初步数据表明，在HIV感染者中，增殖史标记CD57在效应器CD28-CD8+T细胞上异常低，在抑制ART期间增加，但未能正常化。ART期间持续低的CD57缺陷与单核细胞激活和吲哚胺2，3-双加氧酶(IDO)诱导有关，这是增殖性T细胞缺陷的已知驱动因素，并强烈预测在这种情况下死亡率增加。这些CD8+T细胞缺陷与衰老相关的免疫衰老截然不同，后者的典型特征是效应器CD8+T细胞上CD57的增加。这些数据推动了一种假设，即导致接受治疗的HIV疾病中功能适应性免疫缺陷的表型T细胞缺陷与在老年HIV感染者中观察到的完全不同。我们将直接在200名艾滋病毒感染者和100名非艾滋病毒感染者中解决这一假设，具体目标如下：1)确定维持ART介导的病毒抑制的艾滋病毒感染者是否比年龄匹配的艾滋病毒非感染者的疫苗反应性更差，以及这些缺陷是否可以通过早期启动ART来逆转；2)表征表型T细胞缺陷，预测在接受治疗的艾滋病毒感染和老龄化中疫苗反应性较差；以及3)表征先天免疫激活途径与治疗的艾滋病毒感染和老龄化中疫苗反应性较差之间的关系。通过表征HIV感染治疗中疫苗反应性受损的免疫学决定因素，以及它们与衰老相关免疫衰老的差异，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.