Sialic Acid Modulation of HIV-associated Chronic Inflammaging

项目总结：尽管接受了抗逆转录病毒治疗，但HIV相关的慢性炎症状态仍然存在 (ART)并被称为“炎症”。这种炎症是增加HIV+风险的重要因素 个人的年龄和艾滋病毒相关的共病的经验。然而，生理过程 其背后的原因仍然知之甚少。我们一直在研究循环中的糖组学改变是否 糖蛋白在HIV+个体的炎症发病机制中起作用。尤其是聚糖的改变， 已知循环糖蛋白上的唾液酸损失（低唾液酸化）介导炎症， 与生物年龄有关。在最近的一篇文章中，我们发现， HIV+个体血浆中唾液酸化糖蛋白和免疫球蛋白G（IgG）显著减少 （病毒血症和ART抑制）。这很有趣，因为唾液酸化的糖蛋白 已知可能通过抑制TLR 4信号传导来启动抗炎反应。测试是否 与合并症的联系，我们发现低唾液酸化水平与患病率显著相关， HIV+ ART+个体中的几种炎症相关共病。这些数据支持我们 假设HIV感染加速了与年龄相关的低唾液酸化的速度， 到发炎与其他人的工作一致，这表明低唾液酸化不仅与 炎症，但也机械地驱动它，我们表明，硅酸涂层纳米粒子减少免疫 在HIV感染的生理学相关的BLT人源化小鼠模型中的活化/炎症。我们断定 正常化糖基化模式将防止HIV相关炎症的发展。在 目的1：我们将检验以下假设，即与年龄相关的循环糖蛋白和IgG的低唾液酸化， 与艾滋病毒阴性者相比，艾滋病毒阳性者的发病速度加快，并与炎症有关。我们将使用 先进的糖组学技术和良好的动力，横截面，和纵向血浆样本， 特征性的HIV队列（WIHS和MACS），以建立糖代谢之间的纵向关系。 艾滋病毒感染者的年龄、炎症和亚临床动脉粥样硬化的患病率（作为 炎症相关的并发症）。我们还将检验唾液酸酶活性增强的假设， 是HIV+ ART+个体中观察到的低唾液酸化的基础。在目标2中，我们将检验以下假设： 酸包被的纳米颗粒可以在ART抑制的HIV感染期间预防免疫激活/炎症， 使用HIV感染的ART抑制的BLT人源化小鼠。我们还将测试这些效应是否由以下因素介导： 抑制TLR 4信号传导。我们正在利用糖组学新兴领域的最新进展， 阐明艾滋病病毒，衰老，以及ART期间宿主免疫环境之间的联系。我们的目标是建立一个 发现HIV衰老的新型糖基生物标志物和新型糖基生物标志物的新范例 干预措施，以预防炎症和艾滋病毒+个体中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.