T cell depletion in older HIV-infected patients by plasmacytoid dendritic cells

描述（由申请人提供）：在艾滋病毒感染中发现CD4+ t细胞计数下降是艾滋病毒疾病进展的标志，随着高活性抗逆转录病毒疗法的出现，艾滋病毒患者可以活到更老的年龄，已经观察到老年艾滋病毒感染患者（50岁以上）的CD4+和CD8+细胞计数低于年轻艾滋病毒患者。HIV感染期间T淋巴细胞损失的一种机制是通过未感染的旁观者CD4+和CD8+ T细胞的凋亡，这可以通过病毒诱导死亡配体发生，如I型干扰素诱导的tnf相关凋亡诱导配体（TRAIL）。浆细胞样树突状细胞（pDC）是I型干扰素的有效生产者，并且在HIV感染期间也表达TRAIL。由于pDC功能障碍在正常衰老和HIV感染中也很常见，TRAIL是否在正常衰老过程中发挥作用尚不清楚，就像在HIV感染过程中一样。我们假设，在老年HIV感染者中，较低的CD4+和CD8+ t细胞计数部分是由于年龄和HIV感染对慢性pDC生成IFN-¿的累加效应，IFN-¿介导TRAIL（一种死亡配体）的表达。这导致这些细胞的旁观者凋亡，这些细胞的消耗导致免疫功能障碍和对感染的易感性增加。我们建议研究老年艾滋病毒感染者，将他们与年轻艾滋病毒感染者和年龄匹配的对照组进行比较。我们将研究来自hiv感染者的样本，以确定TRAIL表达与pDC活化之间的关系，然后研究老年hiv感染者pDC中TRAIL增强的机制。在我们研究的第二部分，我们将研究老年hiv感染者的T细胞亚群比年轻hiv感染者更容易受到trail介导的细胞凋亡的机制。这项研究的数据将有助于阐明老年患者HIV感染期间pDC功能障碍的机制，以及为什么老年HIV感染者表现出较低的CD4+和CD8+细胞计数，这使得他们的预后比年轻HIV感染者差。

DESCRIPTION (provided by applicant): The decline in CD4+ T-cell counts found in HIV infection is a hallmark of HIV disease progression, and with the advent of highly active anti-retroviral therapy allowing HIV patients to live to older ages, it has been observed that in older patients (>50 years) with HIV infection, CD4+ and CD8+ cell counts are lower than in younger HIV patients. One mechanism of T- lymphocyte loss during HIV infection is through apoptosis of uninfected bystander CD4+ and CD8+ T-cells which can occur through the viral induction of death ligands, such as the type I interferon-inducible TNF-Related Apoptosis Inducing Ligand (TRAIL). Plasmacytoid dendritic cells (pDC) are potent producers of type I interferons and are also known to express TRAIL during HIV infection. With pDC dysfunction also common to normal aging and HIV infection, it is unknown whether TRAIL plays a role during normal aging, as it does during HIV infection. We hypothesize that in older HIV-infected individuals, lower CD4+ and CD8+ T-cell counts are due in part to the additive effects of age and HIV infection on the chronic pDC production of IFN-¿, which mediates the expression of TRAIL, a death ligand. This leads to bystander apoptosis of these cells, with depletion of these cells leading to immune dysfunction and increased susceptibility to infections. We propose to study older HIV-infected subjects, comparing them to younger HIV-infected subjects and age-matched controls. We will study samples from HIV-infected subjects to determine the relationship between TRAIL expression and pDC activation in vivo, then study the mechanisms of TRAIL potentiation in pDC from older HIV-infected subjects. In the second part of our study, we will study the mechanisms by which T cell subsets from older HIV-infected subjects are more susceptible to TRAIL-mediated apoptosis than younger HIV-infected subjects. Data from this study will help elucidate the mechanisms of pDC dysfunction during HIV infection in aged patients, as well as why older HIV-infected individuals exhibit lower CD4+ and CD8+ cell counts that make their prognosis worse than younger HIV-infected individuals. PUBLIC HEALTH RELEVANCE: Though anti-retroviral therapy has allowed people with HIV-infection to live longer lives, these individuals show signs of early aging, including changes in the immune response usually seen in much older individuals. Our work is important because it studies the ways by which the combination of older age and HIV-infection contributes to the loss of T cells, and how plasmacytoid dendritic cells are involved in this process.