Contribution of plasmacytoid DCs to immune senescence in HIV infection

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，艾滋病毒-1感染被认为是一种慢性病，感染艾滋病毒的人可以活几十年。根据监测数据，美国疾病控制与预防中心估计，到2015年，美国整整一半的艾滋病毒携带者将超过50岁。尽管预期寿命发生了戏剧性的变化，但感染艾滋病毒的人的预计寿命仍然比未感染艾滋病毒的人短，他们患有一些与艾滋病毒相关的非艾滋病并存疾病，包括早期发展通常与较高年龄相关的慢性病，如心血管疾病、痴呆症、虚弱和骨折。其中许多缺陷的核心是慢性免疫激活。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、克隆性衰竭、端粒缩短和T细胞的复制性衰老。虽然研究已经在年龄的背景下检查了艾滋病毒感染者的T细胞亚群，但对先天免疫反应的状态知之甚少，而先天免疫反应是发展适应性免疫反应所必需的。特别是在HIV感染的背景下，虽然许多研究都涉及到浆细胞样树突状细胞(PDC)，也有一些研究报道了PDC在人类衰老中的地位，但在HIV和衰老的背景下，PDC的研究尚未见报道。我们的初步数据表明，不仅血液PDC数量以及功能存在年龄相关性缺陷；这些数量和功能缺陷也发生在艾滋病毒感染者中，但通常发生在较早的年龄，老年艾滋病毒感染者受到的损害最大。我们假设慢性免疫激活导致HIV感染者的PDC衰老。在这项研究中，我们将利用两个实验队列来比较HIV血清阳性和血清阴性捐赠者的PDC。第一组将对不同年龄的接受抗逆转录病毒治疗、感染艾滋病毒和未感染的成年受试者进行横断面研究，第二组将对开始抗逆转录病毒治疗前以及接受抗逆转录病毒治疗24周和48周后的个人进行纵向研究。在第一个目标中，我们将研究PDC在这两组中的表型和功能。在第二个目标中，我们将定义PDC CD2+亚群中与年龄和HIV相关的变化，这些亚群积累在老年个体的血液中。最后，在第三个目标中，我们将检查骨髓PDC和PDC前体在年长的和年轻的HIV感染和未感染的个体中的状态，以确定如何一起变化。我们的研究将提供关于PDC在健康老龄化和老龄化与HIV感染中的状态的迫切需要的信息，并可能导致识别免疫衰老的生物标记物和潜在的治疗干预目标。

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.