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

描述（由申请人提供）：HIV感染中发现的CD 4 + T细胞计数下降是HIV疾病进展的标志，随着高效抗逆转录病毒治疗的出现，允许HIV患者活到更大的年龄，已经观察到在患有HIV感染的老年患者（>50岁）中，CD 4+和CD 8+细胞计数低于年轻HIV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CD 4+和CD 8 + T细胞的凋亡，这可以通过病毒诱导死亡配体（例如I型干扰素诱导的TNF相关凋亡诱导配体（TRAIL））而发生。浆细胞样树突状细胞（pDC）是I型干扰素的有效生产者，并且还已知在HIV感染期间表达TRAIL。由于pDC功能障碍在正常衰老和HIV感染中也很常见，因此尚不清楚TRAIL是否在正常衰老中发挥作用，就像在HIV感染中一样。我们假设，在老年HIV感染者中，较低的CD 4+和CD 8 + T细胞计数部分是由于年龄和HIV感染对IFN-γ的慢性pDC产生的叠加效应，IFN-γ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，这些细胞的耗竭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，将他们与年轻的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感染受试者的样本，以确定体内TRAIL表达与pDC活化之间的关系，然后研究来自老年HIV感染受试者的pDC中TRAIL增强的机制。在我们研究的第二部分中，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CD 4+和CD 8+细胞计数，使其预后比年轻HIV感染者更差。

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.