Impact of Sex on Glycosylation-dependent Antibody-mediated Innate Immune Functions During HIV Infection

项目概述：除了中和，抗体可以引发一系列Fc介导的先天性免疫反应， 功能如抗体依赖性细胞介导的细胞毒性（ADCC）、抗体依赖性细胞毒性、抗体依赖性细胞毒性和抗体依赖性细胞毒性。 吞噬作用（ADCP）和抗体依赖性补体沉积（ADCD）。这些先天免疫功能 是有益的，因为它们有助于病原体清除;然而，它们也可以在病毒感染期间诱导炎症。 感染.抗体糖基化强烈影响这些功能。例如，岩藻糖降低ADCC，而 唾液酸和半乳糖具有抗炎作用，并可抑制ADCP和ADCD。在我们的R 01 AG 062383中， 询问衰老过程中的HIV感染是否与特定的IgG糖组学改变有关， 长期抗逆转录病毒治疗（ART）。我们的数据表明，来自HIV+ ART+个体的抗体确实 与未感染HIV的抗体相比， 以与更高的炎症、增强的ADCC/ADCP/ADCD和更高的 亚临床动脉粥样硬化在分析过程中，我们注意到男女之间存在明显差异。 在ART+ HIV感染期间，来自女性的抗体具有较低的抗炎和抗HIV抗体水平。 ADCP/ADCD唾液酸和半乳糖以及抗ADCC岩藻糖水平高于来自 男人生物性别越来越被认为是免疫和疾病的重要调节剂 HIV感染期间的进展。然而，这种现象背后的机制尚不清楚， 重要的是要了解，以设计干预措施，为两性工作。这些数据支持我们的假设 性别依赖性IgG糖基化失调调节Fc介导的先天免疫功能， 抗逆转录病毒疗法抑制HIV感染期间的炎症。我们将以两个目标来检验这一假设： 在目标1中，我们将检验来自女性的抗体驱动更高的ADCP/ADCD、更高的髓样细胞增殖、以及更高的细胞毒性的假设。 炎症，并且ADCC低于男性抗体。我们预计，根据他们的糖组学特征， 女性的抗体将驱动更高的ADCP/ADCD，更高的骨髓炎症和更低的ADCC， 男性的抗体。我们也预期这些不同的能力将与更高的炎症有关 和炎症相关病症。在目的2中，我们将检验来自于人的糖工程化IgG的假设。 女性和男性可以调节抗HIV特异性Fc介导的先天免疫功能和炎症。我们 最近实施了一种化学-酶促改变抗体糖基化的方法。我们将使用这个 改变来自男性和女性的抗体的糖基化并测试糖工程化的能力的方法 抗体引发特异性先天免疫功能和炎症。我们认为抗体的特征 类似于女性的那些（低唾液酸/半乳糖）将引起高ADCD/ADCP活性和炎症。在 总之，这一补充将确定新的糖和免疫途径，可以调节， 开发针对艾滋病毒老化期间免疫功能和炎症的性意识/特异性治疗。

PROJECT SUMMARY: Beyond neutralization, antibodies can elicit an array of Fc-mediated innate immune functions such as antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent complement deposition (ADCD). These innate immune functions are beneficial, as they contribute to pathogen clearance; however, they also can induce inflammation during viral infections. Antibody glycosylation strongly impacts these functions. For example, fucose reduces ADCC, while sialic acid and galactose are anti-inflammatory and may inhibit ADCP and ADCD. In our R01 AG062383, we asked whether HIV infection during aging is associated with specific IgG glycomic alterations that persist despite long-term antiretroviral therapy (ART). Our data show that antibodies from HIV+ ART+ individuals do indeed exhibit specific glycomic alterations (loss of galactose and fucose) compared to antibodies from HIV-uninfected counterparts in a manner linked to higher inflammation, enhanced ADCC/ADCP/ADCD, and higher incidence of subclinical atherosclerosis. During this analysis, we noticed apparent differences between women and men. During ART+ HIV infection, antibodies from women have a lower level of the anti-inflammatory and anti- ADCP/ADCD sialic acid and galactose and higher levels of the anti-ADCC fucose compared to antibodies from men. Biological sex has increasingly been recognized as an important modulator of immunity and disease progression during HIV infection. However, the mechanisms underlying this phenomenon are unknown but important to understand to design interventions that work for both sexes. These data support our hypothesis that sex-dependent IgG glycomic dysregulation modulates Fc-mediated innate immune functions and inflammation during ART-suppressed HIV infection. We will test this hypothesis with two aims: In Aim 1, we will test the hypothesis that antibodies from women drive higher ADCP/ADCD, higher myeloid inflammation, and lower ADCC than antibodies from men. We expect, based on their glycomic profile, that antibodies from women will drive higher ADCP/ADCD, higher myeloid inflammation, and lower ADCC than antibodies from men. We also expect that these differential abilities will be associated with higher inflammation and inflammation-associated conditions. In Aim 2, we will test the hypothesis that glycoengineered IgGs from women and men can modulate anti-HIV specific Fc-mediated innate immune functions and inflammation. We recently implemented a method to chemo-enzymatically alter the glycosylation of antibodies. We will use this method to alter the glycosylation of antibodies from men and women and test the ability of glycoengineered antibodies to elicit specific innate immune functions and inflammation. We expect that antibodies with profiles similar to those of women (low sialic acid/galactose) will elicit high ADCD/ADCP activities and inflammation. In Summary, this supplement will identify novel glycomic and immunological pathways that can be modulated to develop sex-aware/specific treatments that target immune functions and inflammation during aging with HIV.