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

• 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
• 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

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：尽管有最佳的抗逆转录病毒治疗（ART）， hiv感染者的死亡率和一些与衰老相关的发病率的风险仍然比一般人群高。治疗后的HIV感染的慢性炎症状态似乎可以预测许多这些疾病，也被认为会导致过早的“免疫衰老”，这是一种功能性T细胞缺陷，通常在年龄更大的未感染HIV的个体中看到。然而，在治疗的HIV感染中损害功能性免疫反应的特异性T细胞缺陷是未知的，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，CD28- CD8+ T细胞的增殖历史标志物CD57异常低，在抑制性抗逆转录病毒治疗期间增加，但未能正常化。抗逆转录病毒治疗期间持续的低CD57缺陷与单核细胞活化和吲哚胺2,3-双加氧酶（IDO）诱导有关，这是已知的增殖性T细胞缺陷的驱动因素，并强烈预测这种情况下死亡率的增加。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CD8+ T细胞上CD57的增加。这些数据激发了一种假设，即在接受治疗的HIV疾病中，导致功能性适应性免疫缺陷的表型T细胞缺陷与在老年HIV感染者中观察到的表型T细胞缺陷截然不同。我们将在200名艾滋病毒感染者和100名未感染艾滋病毒者的队列中直接解决这一假设，具体目标如下：1)确定维持ART介导的病毒抑制的HIV感染者是否比年龄匹配的HIV未感染者具有更差的疫苗反应性，以及这些缺陷是否可以通过早期开始ART来逆转；2)表征预测治疗HIV感染和衰老中疫苗反应性差的表型T细胞缺陷。3)确定HIV感染治疗后的先天免疫激活途径与疫苗反应性差和衰老之间的关系。通过描述受治疗的艾滋病毒感染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的免疫衰老有何不同，该项目将有助于确定新的干预措施的目标，以恢复艾滋病毒感染者的免疫功能和健康。