Determinants of Functional Immune Defects in Treated HIV Infection and Aging

HIV 感染治疗和衰老过程中功能性免疫缺陷的决定因素

基本信息

批准号：
8784045
负责人：
PETER W HUNT
金额：
$ 78.95万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8784045
关键词：
Acute Address Adult Age Aging Aging-Related Process Antigens Attenuated CD28 gene CD8B1 gene Cell Count Cell Proliferation Cells Characteristics Chronic Coagulation Process Cytomegalovirus Data Defect Disease Elderly Fibrosis Frequencies General Population HIV HIV Infections Health Heart Immune Immune response Immune system Immunologics In Vitro Individual Infection Inflammation Inflammatory Influenza vaccination Intervention Lead Length Life Life Expectancy Link Lymphoid Mediating Memory Morbidity - disease rate Osteoporosis Pathway interactions Phenotype Population Principal Investigator Recording of previous events Research Personnel Risk Stem cells T cell differentiation T memory cell T-Cell Proliferation T-Lymphocyte Toxic effect Tryptophan 2,3 Dioxygenase Vaccines Viral Work antiretroviral therapy cohort high risk immune activation immune function immunosenescence improved infection related cancer inflammatory marker influenza virus vaccine lifestyle factors loss of function microbial monocyte mortality novel premature prevent public health relevance regenerative response seasonal influenza senescence telomere

项目摘要

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.

描述：尽管最佳的抗逆转录病毒疗法（ART），与普通人群相比，受HIV感染的个体继续增加死亡率和几种与衰老相关的病因。治疗的HIV感染的慢性炎症状态似乎预测了许多这些病因，也被认为会导致过早的“免疫衰老”，这是在许多老年HIV未感染的个体中通常看到的功能性T细胞缺陷。然而，在治疗的HIV感染中损害功能免疫反应的特定T细胞缺陷尚不清楚，并且可能与衰老中观察到的那些差异很大。我们小组的初步数据表明，在HIV感染的个体中，效应子CD28- CD8+ T细胞的增殖历史标记CD57异常低，在抑制性艺术期间增加，但未能正常化。 ART期间这种持续低的CD57缺陷与单核细胞激活和吲哚胺2,3-二氧酶（IDO）诱导有关，已知的增殖T细胞缺陷驱动因素，并强烈预测这种情况下的死亡率增加。这些CD8+ T细胞缺陷与与衰老相关的免疫衰老完全不同，通常以效应子CD8+ T细胞上CD57的增加为特征。这些数据激发了以下假设：在治疗的HIV疾病中负责功能适应性免疫缺陷的表型T细胞缺陷与在感染的HIV老年人感染的个体中观察到的疾病完全不同。我们将直接在200个具有以下特定目的的200个HIV感染和100个HIV未感染的个体中解决这一假设：1）确定维持ART ART介导的病毒抑制的HIV感染的个体是否具有较差的疫苗反应性较差，而与年龄相匹配的HIV未发现的个体相比，这些缺陷及其早期的疫苗能够互相互动，是否可以通过ART的早期启动来揭示ART的隔离效果。治疗的HIV感染和衰老的反应性，以及3）表征先天免疫激活途径与治疗的HIV感染和衰老中疫苗反应不良之间的关系。通过表征治疗的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反应能力，该项目将有助于确定新的干预措施的目标，以恢复感染HIV感染的个体的免疫功能和健康。