Antibody-Mediated Suppression of Antiviral Inflammasome Activation

描述：虽然HAART降低了HIV相关的发病率和死亡率，但越来越多的证据表明，慢性炎症性内科疾病，包括心血管疾病、糖尿病、慢性肾脏和肝脏疾病、骨质疏松症和癌症，在HIV感染者中更频繁和/或更早发生。慢性丙型肝炎同样与肝脏炎症和糖尿病、肾脏疾病和癌症风险增加有关。与单独感染丙型肝炎病毒相比，HIV与丙型肝炎病毒混合感染导致炎症相关的肝和肾脏病理进展更快。然而，HIV-1和丙型肝炎病毒相关的慢性炎症的发病机制是复杂的，而且还不完全清楚。感染中的炎症是由检测微生物分子的先天免疫细胞信号受体协调的。细胞内免疫受体的一个子集可以组装成称为“炎性小体”的多蛋白质复合体。炎症体整合了两个病原体触发的信号级联(信号1和2)，最终导致促炎细胞因子IL-18和IL-1的活性成熟形式的分泌。血清IL-18水平升高与糖尿病、肾脏疾病和肝脏炎症以及动脉粥样硬化进展加快有关。我们最近发现，艾滋病毒和丙型肝炎病毒粒子在单核细胞和巨噬细胞中组装炎性小体，并且针对这两种病毒包膜蛋白的抗体亚集可以阻止单核细胞对同源病毒的反应释放IL-18和IL-1。针对艾滋病毒或丙型肝炎病毒的抗体通过什么机制防止同源病毒激活炎症体，以及什么抗体特征对这一过程至关重要，目前尚不清楚。鉴于HIV感染者中炎症性疾病的发生率增加，我们的总体目标是提高我们对炎性小体抑制机制的了解，以加强对HIV相关炎症的控制。在目标1中，我们将通过比较艾滋病毒感染、丙型肝炎病毒感染、艾滋病毒/丙型肝炎病毒混合感染和未感染的受试者血浆中IL-18、IL-1和其他促炎细胞因子的水平，来测试与单一感染相比，联合感染是否增加炎症体的激活。使用一个新的模型系统，我们将评估艾滋病毒和丙型肝炎病毒特异性抗体在这两种病毒存在的情况下对单核细胞炎症体激活的影响。在目标2中，我们将确定包膜抗体是否阻断病原体触发的信号级联中的一个或两个信号，并将炎症体抑制的程度与两个信号的抑制相关联。在《目标3》中，我们将 确定抗包膜抗体恒定区(Fc)在抑制炎症小体中的作用。这些研究将通过揭示慢性病毒引发的炎症刺激和调节机制而开辟新的天地，潜在地解释肝脏、肾脏和其他器官炎症增加的原因，并为调节这种炎症提供新的治疗靶点。

DESCRIPTION: While HAART has reduced the incidence of HIV-related morbidity and mortality, increasing evidence suggests that chronic inflammatory medical illnesses, including cardiovascular disease, diabetes mellitus, chronic kidney and liver disease, osteoporosis, and cancer occur more frequently and/or at earlier ages in HIV infected individuals. Chronic HCV is similarly associated with liver inflammation and increased risk of diabetes mellitus, kidney disease, and cancer. HIV co-infection with HCV results in enhanced progression of inflammation-linked liver and kidney pathology relative to HCV infection alone. However, the pathogenesis of HIV-1 and HCV-related chronic inflammation is complex and incompletely understood. Inflammation in infection is orchestrated by innate immune cell signaling receptors that detect microbial molecules. A subset of intracellular immune receptors can assemble into multi-protein complexes called "inflammasomes". Inflammasomes integrate two pathogen-triggered signaling cascades (signal 1 and 2), ultimately leading to secretion of the active, mature forms of the pro-inflammatory cytokines interleukin (IL)-18 and IL-1¿. Elevated serum IL-18 levels are associated with diabetes, with kidney disease and liver inflammation, and with increased atherosclerosis progression. We recently discovered that HIV and HCV virions assemble inflammasomes in monocytes and macrophages and that a subset of antibodies directed against envelope proteins from either virus can prevent monocyte IL-18 and IL-1¿ release in response to cognate virus. The mechanism through which antibodies specific for HIV or HCV prevent activation of the inflammasome by cognate virus and what antibody characteristics are critical for the process are unknown. Given the increased rates of inflammatory diseases in HIV infected people, our overall goal is to improve our understanding of mechanisms of inflammasome suppression to enhance control of HIV-associated inflammation. In Aim 1, we will test whether co-infection increases inflammasome activation relative to monoinfection by comparing IL-18, IL-1¿, and other proinflammatory cytokine levels in plasma from HIV infected, HCV infected, HIV/HCV co-infected, and uninfected subjects. Using a novel model system, we will assess the effect of HIV and HCV specific-antibodies on monocyte inflammasome activation with both viruses present. In Aim 2, we will determine if envelope antibodies block one or both signals in the pathogen-triggered signaling cascades and correlate the degree of inflammasome inhibition to inhibition of the two signals. In Aim 3, we will determine the role of the constant region (Fc) of anti-envelope antibodies in inflammasome inhibition. These studies will break new ground by revealing mechanisms of stimulation and modulation of inflammation triggered by chronic viruses, potentially explaining increased inflammation of the liver, kidney, and other organs and providing new therapeutic targets for modulation of that inflammation.