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：当艾滋病毒在美国开始流行时，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，感染HIV的人可以活几十年。根据监测数据，疾病预防控制中心估计，到2015年，美国一半的艾滋病毒感染者将超过50岁。尽管预期寿命发生了巨大变化，但艾滋病毒感染者的预期寿命仍然比未感染者短，他们患有许多与艾滋病毒有关的非艾滋病并发症，包括通常与更高年龄有关的慢性疾病的早期发展，包括心血管疾病，痴呆症，虚弱和骨折。许多这些缺陷的核心是慢性免疫激活。此外，有证据表明T细胞区室的加速衰老，包括幼稚T细胞的损失、克隆耗竭、缩短的端粒和T细胞的复制性衰老。虽然研究已经在年龄背景下检查了HIV感染个体中的T细胞区室，但对先天免疫应答的状态知之甚少，这是适应性免疫应答发展所必需的。特别是，虽然许多研究已经解决了浆细胞样树突状细胞（pDC）在HIV感染的背景下，和一些研究已经报道了pDC在人类衰老的状态，没有任何关于pDC在HIV和衰老的背景下报道。我们的初步数据表明，不仅血液pDC数量，而且功能也存在年龄依赖性缺陷;这些数量和功能缺陷也发生在HIV感染个体中，但通常发生在较早的年龄，并且年龄较大的HIV感染个体受损最严重。我们假设慢性免疫激活驱动HIV感染者的pDC衰老。在本研究中，我们将利用两个实验群组来比较来自HIV血清阳性和血清阴性供体的pDC。第一组将是对不同年龄的ART治疗的、HIV感染和未感染的成人受试者的横断面研究，而第二组将是对开始ART之前和ART治疗24周和48周之后的个体的纵向研究。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CD 2+亚群中与年龄和HIV相关的变化，这些变化在衰老个体的血液中积累。最后，在第三个目标中，我们将检查老年与年轻HIV感染和未感染个体的骨髓pDC和pDC前体的状态，以确定如何变化。我们的研究将提供关于健康老龄化和HIV感染老龄化中pDC状态的急需信息，并可能导致识别免疫衰老的生物标志物和治疗干预的潜在靶点。