Sialic Acid Modulation of HIV-associated Chronic Inflammaging

项目摘要：尽管接受了抗逆转录病毒治疗，但艾滋病毒相关的慢性炎症状态仍然存在 (艺术)，并被称为‘煽动性’。这种炎症是增加HIV+风险的一个重要因素 与年龄和艾滋病毒相关的共病的个人经历。然而，生理过程 人们对其背后的原因仍知之甚少。我们一直在调查循环中的血糖变化 糖蛋白在HIV阳性个体的炎症发病机制中发挥作用。尤其是糖链的改变， 已知循环糖蛋白上唾液酸的丢失(低唾液酸化)可介导炎症和 与生物年龄有关。在最近的一篇文章中，我们发现循环中的抗炎水平 HIV感染者血浆唾液酸化糖蛋白和免疫球蛋白G显著降低 (病毒和ART抑制)与艾滋病毒对照组相比。这很耐人寻味，因为唾液酸糖蛋白 已知可以启动抗炎反应，可能是通过抑制TLR4信号。测试 与共病有关，我们发现低唾液酸化水平与患病率显著相关。 在HIV+ART+个体中的几种与炎症相关的共病。这些数据支持我们的 假设艾滋病毒感染加速了与年龄相关的唾液过少的速度，这对 为火爆干杯。与其他人的工作一致，表明低唾液酸化不仅与 炎症，但也是机械驱动它，我们表明，唾液酸包被的纳米颗粒降低免疫 生理相关的BLT人源化小鼠HIV感染模型中的激活/炎症。我们假设 糖基化模式正常化将防止艾滋病毒相关炎症的发展。在……里面 目的1我们将检验一种假设，即与年龄相关的循环糖蛋白和免疫球蛋白低唾液酸化是 与艾滋病毒携带者相比，艾滋病毒携带者加速感染，并与炎症有关。我们将使用 先进的血糖分析技术和优质的横截面和纵向血浆样本 表征HIV(WIHS和MACs)队列，建立血糖之间的纵向关系 概况、艾滋病毒老化、炎症和亚临床动脉粥样硬化的患病率(例如 炎症相关的共同发病)。我们还将检验唾液酸酶活性增强的假设 这是在HIV+ART+个体中观察到的低唾液酸化的基础。在目标2中，我们将检验唾液酸化的假设 酸性包裹的纳米颗粒可以防止ART抑制的HIV感染期间的免疫激活/炎症， 使用HIV感染、ART抑制的BLT人源化小鼠。我们还将测试这些影响是否由 抑制TLR4信号转导。我们正在利用新兴的糖组学领域的最新进展来 阐明艾滋病病毒、衰老和抗逆转录病毒治疗期间宿主免疫环境之间的关系。我们的目标是创建一个 发现新的基于糖链的艾滋病毒衰老生物标志物和新的基于糖链的生物标志物的新范式 干预措施，以预防艾滋病毒阳性个体的炎症和与衰老相关的疾病的发展。

PROJECT SUMMARY: An HIV-associated state of chronic inflammation persists despite antiretroviral therapy (ART) and is termed ‘inflammaging’. Such inflammation is a significant contributor to the increased risk HIV+ individuals’ experience of age- and HIV-associated co-morbidities. However, the physiological processes underlying it remain poorly understood. We have been investigating whether glycomic alterations in circulating glycoproteins play a role in the pathogenesis of inflammation in HIV+ individuals. Glycan alterations, in particular, loss of sialic acid (hypo-sialylation), on circulating glycoproteins are known to mediate inflammation and associate with biological age. In a recent publication, we found that levels of circulating, anti-inflammatory sialylated glycoproteins and immunoglobulins G (IgGs) are markedly reduced in the plasma of HIV+ individuals (viremic and ART-suppressed) compared to HIV- controls. This was intriguing because sialylated glycoproteins are known to initiate an anti-inflammatory response, possibly by inhibiting TLR4 signaling. Testing for a connection with co-morbidities, we found that levels of hypo-sialylation significantly correlate with the prevalence of several inflammation-associated co-morbidities in HIV+ ART+ individuals. These data support our hypothesis that HIV infection accelerates the pace of age-associated hypo-sialyation, which contributes to inflammaging. Consistent with the work of others suggesting that hypo-sialyation not only correlates with inflammation, but also mechanistically drive it, we showed that sialic-acid coated nanoparticles reduce immune activation/inflammation in the physiologically-relevant BLT humanized mouse model of HIV infection. We posit that normalizing glycosylation patterns will prevent the development of HIV-associated inflammation. In Aim 1 we will test the hypothesis that age-associated hypo-sialylation of circulating glycoproteins and IgGs is accelerated in HIV+ individuals compared to HIV- counterparts and is linked to inflammaging. We will use advanced glycomic technologies and well-powered, cross-sectional, and longitudinal plasma samples from well- characterized cohorts of HIV (WIHS and MACS), to establish a longitudinal relationship between glycomic profiles, aging with HIV, inflammation, and the prevalence of subclinical atherosclerosis (as an example of inflammation-associated co-morbidity). We also will test the hypothesis that enhanced activity of sialidase underlies the hypo-sialyation observed in HIV+ ART+ individuals. In Aim 2, we will test the hypothesis that sialic acid coated nanoparticles can prevent immune activation/inflammation during ART-suppressed HIV infection, using HIV-infected, ART-suppressed BLT humanized mice. We will also test if these effects are mediated by inhibiting TLR4 signaling. We are taking advantage of recent advances in the emerging field of glycomics to clarify the association between HIV, aging, and the host immune environment during ART. We aim to create a new paradigm for discovering novel glycomic-based biomarkers of aging with HIV and novel glycan-based interventions to prevent inflammation and the development of aging-related conditions in HIV+ individuals.