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的CD4+T细胞计数的下降是艾滋病毒疾病进展的一个标志，随着高效抗逆转录病毒疗法的出现使艾滋病毒患者能够活到更高的年龄，人们观察到，在感染艾滋病毒的老年患者(&gt；50岁)中，CD4+和CD8+细胞计数低于年轻的艾滋病毒患者。HIV感染过程中T淋巴细胞丢失的一种机制是通过病毒诱导死亡配体(如I型干扰素诱导的肿瘤坏死因子相关凋亡诱导配体(TRAIL))使未感染的旁观者CD4+和CD8+T细胞发生凋亡。浆细胞样树突状细胞(PDC)是I型干扰素的有效制造者，也被认为在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，目前尚不清楚TRAIL在正常衰老过程中是否像在HIV感染过程中一样发挥作用。我们推测，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产生干扰素-β的相加效应，干扰素-β介导死亡配体TRAIL的表达。这会导致这些细胞的旁观者凋亡，这些细胞的枯竭会导致免疫功能障碍，增加感染的易感性。我们建议研究年长的艾滋病毒感染者，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HIV感染者的样本，以确定体内TRAIL表达与PDC激活的关系，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感染艾滋病毒期间PDC功能障碍的机制，以及为什么老年艾滋病毒感染者表现出较低的CD4+和CD8+细胞计数，从而使他们的预后比年轻艾滋病毒感染者更差。 与公共卫生相关：虽然抗逆转录病毒疗法使艾滋病毒感染者能够活得更长，但这些人表现出过早衰老的迹象，包括通常在年长得多的人身上看到的免疫反应的变化。我们的工作很重要，因为它研究了老年和艾滋病毒感染相结合导致T细胞丧失的方式，以及浆细胞样树突状细胞如何参与这一过程。

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.