Contribution of plasmacytoid DCs to immune senescence in HIV infection

浆细胞样 DC 对 HIV 感染中免疫衰老的影响

• 批准号: 9097638
• 负责人: PATRICIA FITZGERALD-BOCARSLY
• 金额: $ 39.75万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9097638
• 关键词: Address; Adult; Affect; Age; Age-Years; Aging; Anti-Retroviral Agents; Atherosclerosis; Blood; Bone Marrow; Cardiovascular Diseases; Cell Aging; Cell Count; Cells; Centers for Disease Control and Prevention (U.S.); Characteristics; Chronic; Chronic Disease; Comorbidity; Cross-Sectional Studies; Data; Dementia; Dendritic Cells; Depressed mood; Development; Diabetes Mellitus; Disease; Elderly; Epidemic; Exhibits; Face; Fracture; Frequencies; HIV; HIV Infections; HIV Seropositivity; HIV-1; Health; Herpesvirus 1; Human; Immune; Immune response; Immune system; Individual; Infection; Inflammation; Inflammatory; Interferons; Lead; Life; Life Expectancy; Longevity; Longitudinal Studies; Monitor; Newly Diagnosed; Osteoporosis; Patients; Phase; Phenotype; Population; Predisposition; Premature aging syndrome; Production; Reporting; Risk; Stimulus; T-Lymphocyte; Telomere Shortening; Testing; Therapeutic Intervention; United States; Virus Replication; adaptive immunity; age effect; age related; aging population; antiretroviral therapy; base; biomarker identification; cadmium ion; cohort; exhaustion; frailty; functional status; healthy aging; high risk; immune activation; immune function; normal aging; older patient; peripheral blood; premature; reconstitution; research study; senescence; seropositive; specific biomarkers; success; surveillance data; targeted treatment; therapy design; vaccine response; young adult

DESCRIPTION: When the HIV epidemic began in the US, this disease mostly affected younger adults. Now, with the advent of effective anti-retroviral therapies, HIV-1 infection is considered o be a chronic disease and individuals with HIV infection are living for decades. Based on surveillance data, the CDC has estimated that by 2015, fully half of the individuals living with HIV in the US will be over the age of 50. Despite this dramatic shift in life expectancy, individuals with HIV infection still have a projected lifespan that is shorter than their uninfecte counterparts and they suffer from a number of HIV-associated non-AIDS co-morbidities including early development of chronic diseases normally associated with more advanced age including cardiovascular disease, dementia, frailty and fractures. Central to many of these deficiencies is chronic immune activation. Moreover, there is evidence for accelerated senescence of the T cell compartment, including loss of naive T cells, clonal exhaustion, shortened telomeres and replicative senescence of T cells. Although studies have examined the T cell compartment in HIV infected individuals in the context of age, very little is known about the status of the innate immune response, which is required for development of adaptive immune responses. In particular, although many studies have address plasmacytoid dendritic cells (pDC) in the context of HIV infection, and a few studies have reported on pDC status in human aging, nothing has been reported about pDC in the context of HIV and aging. Our preliminary data demonstrate an age-dependent deficiency of not only blood pDC numbers, but also function; these numerical and functional deficiencies also occurred in HIV infected individuals, but often at earlier ages, and with the older HIV- infected individuals the most compromised. We hypothesize that chronic immune activation drives pDC senescence in HIV-infected subjects. In this study we will utilize two experimental cohorts to compare pDC from HIV seropositive and seronegative donors. The first group will be a cross-sectional study of ART- treated, HIV infected and uninfected adult subjects of different ages, while the second group will be a longitudinal study of individuals prior to initiation of ART and after 24 and 48 weeks of ART therapy. In the first aim, we will investigate the phenotype and function of pDC in these two groups. In the second aim, we will define the age- and HIV-related changes in the CD2+ subpopulation of pDC, which accumulate in the blood of aging individuals. Finally, in the third aim, we will examine the status of the bone marrow pDC and pDC precursors in older vs. young HIV-infected and uninfected individuals to determine how changes Together, our studies will provide much-needed information on the status of pDC in healthy aging and aging with HIV infection and may lead to identification of biomarkers for immune senescence and potential targets for therapeutic intervention.

描述：当艾滋病毒流行开始于美国时，这种疾病主要影响年轻人。现在，随着有效的抗逆转录病毒疗法的出现，HIV-1感染被认为是一种慢性疾病，患有HIV感染的人已经生活了数十年。 Based on surveillance data, the CDC has estimated that by 2015, fully half of the individuals living with HIV in the US will be over the age of 50. Despite this dramatic shift in life expectancy, individuals with HIV infection still have a projected lifespan that is shorter than their uninfecte counterparts and they suffer from a number of HIV-associated non-AIDS co-morbidities including early development of chronic diseases normally associated with more advanced年龄在内，包括心血管疾病，痴呆症，脆弱和骨折。这些缺陷中许多缺陷的中心是慢性免疫激活。此外，有证据表明T细胞室加速衰老，包括幼稚T细胞的丧失，克隆疲劳，端粒缩短和T细胞的复制性衰老。尽管研究在年龄的背景下研究了HIV感染个体的T细胞室，但对先天免疫反应的状态知之甚少，这是自适应免疫反应发展所必需的。特别是，尽管许多研究在HIV感染的背景下涉及浆细胞类动物树突状细胞（PDC），并且已经报道了一些有关人类衰老中PDC状态的研究，但在HIV和衰老的背景下，没有任何有关PDC的报道。我们的初步数据表明，不仅是血液PDC数的年龄依赖性缺陷，而且还具有功能。这些数值和功能性缺陷也出现在艾滋病毒感染的个体中，但通常在早期，而较老的艾滋病毒感染者受到最大的损害。我们假设慢性免疫激活驱动了HIV感染受试者的PDC衰老。在这项研究中，我们将利用两个实验队列比较来自HIV血清阳性和血清质供体的PDC。第一组将是对不同年龄的艺术治疗，感染艾滋病毒感染和未感染的成年受试者的横断面研究，而第二组将在开始艺术之前对个体进行纵向研究，以及经过24和48周的艺术治疗。在第一个目标中，我们将研究这两组中PDC的表型和功能。在第二个目标中，我们将定义PDC的CD2+亚群中与年龄和HIV相关的变化，这些变化积聚在老龄化个体的血液中。最后，在第三个目标中，我们将研究骨髓PDC和PDC前体在年龄较大的与年轻的HIV感染和未感染的个体中，以确定如何共同变化，我们的研究将提供有关PDC在健康衰老中的状态的急需信息，以使HIV感染的健康衰老状态，并可能导致生物标记物的生物标志物，以确定对免疫剂量的识别，以实现潜在的污染和潜在的目标。