Contribution of plasmacytoid DCs to immune senescence in HIV infection

描述：当艾滋病在美国开始流行时，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，美国疾病控制与预防中心估计，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比未感染的人短，而且他们患有许多与艾滋病毒相关的非艾滋病并发症，包括通常与高龄相关的慢性病的早期发展，包括心血管疾病、痴呆、虚弱和骨折。这些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细胞的损失，克隆衰竭，端粒缩短和T细胞的复制性衰老。尽管研究已经检查了年龄背景下HIV感染者的T细胞区室，但对先天免疫反应的状态知之甚少，而先天免疫反应是适应性免疫反应发展所必需的。特别是，尽管许多研究都在HIV感染背景下研究了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，但关于pDC在HIV和衰老背景下的作用还没有报道。我们的初步数据表明，血液中pDC的缺乏不仅与年龄有关，而且与功能有关；这些数量和功能缺陷也发生在艾滋病毒感染者身上，但往往发生在较早的年龄，年龄较大的艾滋病毒感染者最容易受到损害。我们假设慢性免疫激活驱动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来比较HIV血清阳性和血清阴性供者的pDC。第一组将是对接受抗逆转录病毒治疗、艾滋病毒感染和未感染的不同年龄的成人受试者进行横断面研究，而第二组将是对开始抗逆转录病毒治疗前和接受抗逆转录病毒治疗24周和48周后的个体进行纵向研究。在第一个目的中，我们将研究这两组pDC的表型和功能。在第二个目标中，我们将定义pDC中CD2+亚群的年龄和hiv相关变化，这些变化在衰老个体的血液中积累。最后，在第三个目标中，我们将检查老年人与年轻HIV感染者和未感染者骨髓pDC和pDC前体的状态，以确定如何变化。总之，我们的研究将提供pDC在健康衰老和HIV感染衰老中的状态急需的信息，并可能导致识别免疫衰老的生物标志物和潜在的治疗干预靶点。

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.