Role of IL-6 and IL-1b in immune dysfunction during aging, HIV, and HCV infection

接受治疗的老年人慢性全身炎症与免疫功能障碍和疾病有关 艾滋病毒感染和丙型肝炎病毒感染。我们认为循环中的炎性蛋白导致免疫衰竭。 和衰老，并导致这些患者群体中出现的免疫功能障碍。近400万 美国人感染丙型肝炎病毒(丙型肝炎病毒)美国退伍军人感染丙型肝炎病毒的平均年龄为 快65岁了。尽管新的不含干扰素的直接作用抗病毒疗法在清除病毒方面非常有效 对于患者来说，几十年的感染和肝脏损伤给患者留下了后果，这就是 目前尚不清楚可溶的炎症介质持续多久，免疫功能障碍和 相关的发病率会持续下去。同样，即使是成功控制了病毒的艾滋病毒感染者 使用抗逆转录病毒治疗数十年的复制增加了死亡率和发病率以及持续性炎症。退伍军人事务部 是美国最大的艾滋病毒护理单一提供者。了解是什么导致了持续的发病率 这些资深患者群体是至关重要的。老年人、丙型肝炎病毒感染者和艾滋病毒感染者都有慢性 免疫性炎症和这三个患者组有许多相同的共病，包括 心血管疾病、癌症和肝病。此CDA-2应用程序的项目设计基于 了解慢性病毒感染患者和老年患者血浆慢性升高 IL-6水平，以及我们最近的数据显示艾滋病毒感染者淋巴中IL-1β水平升高 病人。本研究的中心目标是确定IL-6和IL-1β的潜在机制 有助于免疫衰竭和衰老的发展，并研究潜在的治疗方法 暂时阻断IL-6和IL-1β在慢性感染中改善免疫功能和恢复的作用 精疲力竭或衰老的T细胞。假设在衰老过程中IL-6和IL-1β水平的慢性升高， 丙型肝炎病毒感染和艾滋病毒感染导致免疫衰老和衰竭，从而导致免疫 功能障碍将在3个具体目标中进行测试。目标1将确定T细胞的表型和功能 在体外暴露于IL-1β或IL-6，方法是对疲劳或衰老标志物阳性的细胞进行分选 (PD-1、CD57、TIM-3、KLRG1、LAG3)，并检测其功能以确定是否存在炎症 细胞因子本身就可以推动衰老，与抗原暴露无关。目标2A将检查该表达式 力竭和衰老标志物水平以及细胞内细胞因子的产生与 丙型肝炎病毒感染者、治疗后艾滋病毒感染者淋巴细胞衰老相关分泌表型(SASP) 对老年患者进行流式细胞仪检测。目标2B将检查免疫的恢复和正常化 抗逆转录病毒治疗后HIV感染患者和丙型肝炎病毒感染患者治疗后的纵向功能 启动不含干扰素的直接作用抗病毒治疗。在目标3中，我们将使用慢性病毒的小鼠模型 测定晚期阻断IL-6和IL-1β对力竭发展的影响 和衰老的T细胞，恢复T细胞的功能和增殖能力。候选人的长期任期 目标是了解慢性炎症对健康的影响，免疫系统 系统维持动态平衡，以及炎症如何破坏免疫系统重建的能力 感染后和衰老过程中的动态平衡。这一重点支持了全国范围内日益增长的需求，以推进我们的 了解和制定患有和不患有慢性病毒的老年退伍军人的治疗策略 感染。应聘者的职业目标是利用这个职业发展奖成功过渡到 路易斯·斯托克斯·克利夫兰VAMC的一名独立调查员，并建立了一个富有成效、蓬勃发展的 在退伍军人制度方面的国家领先研究计划。

Chronic systemic inflammation is associated with immune dysfunction and morbidities in the elderly, treated HIV infection, and HCV infection. We propose that circulating inflammatory proteins drive immune exhaustion and senescence and contribute to the immune dysfunction seen in these patient groups. Nearly 4 million Americans are infected with Hepatitis C Virus (HCV) and the mean age of US veterans infected with HCV is nearing 65 years. Although the new IFN-free direct-acting antiviral therapy is highly effective at clearing virus from patients, the patients are left with the consequences of decades of infection and liver damage, and it is still unclear how long soluble mediators of inflammation persist, and how long immune dysfunction and associated morbidity lasts. Similarly, even HIV-infected patients that have successfully controlled viral replication with ART for decades have increased mortality and morbidity and persistent inflammation. The VA is the largest single provider of HIV care in the US. Understanding what causes the continued morbidity in these veteran patient populations is critical. The elderly, HCV and HIV-infected patients all have chronic immune inflammation and these three patient groups share many of the same comorbidities including cardiovascular disease, cancer, and liver disease. The project design of this CDA-2 application is based on the understanding that patients with chronic viral infections and elderly patients show chronic elevated plasma levels of IL-6, and our more recent data demonstrating elevated levels of IL-1β in lymph nodes of HIV-infected patients. The central goals of this study are to determine the underlying mechanisms of IL-6 and IL-1β that contribute to the development of immune exhaustion and senescence and to examine the potential therapeutic role of temporarily blocking IL-6 and IL-1β during chronic infection to improve immune function and recovery of exhausted or senescent T cells. The hypothesis that chronic elevated levels of IL-6 and IL-1β during aging, HCV infection and HIV infection contribute to immune senescence and exhaustion and resulting immune dysfunction will be tested in 3 specific Aims. Aim 1 will determine the phenotype and function of T cells that have been exposed to IL-1β or IL-6 in vitro by sorting the cells positive for exhaustion or senescent markers (PD-1, CD57, Tim-3, KLRG1, Lag3) and examining their functional abilities to determine if inflammatory cytokines alone can drive senescence, independent of antigen exposure. Aim 2A will examine the expression levels of exhaustion and senescent markers and the intracellular production of cytokines associated with the senescence-associated secretory phenotype (SASP) in lymphocytess from HCV-infected, treated HIV-infected, and elderly patients by flow cytometry. Aim 2B will examine the recovery and normalization of immune function, longitudinally, in HIV-infected patients after initiation of ART and in HCV-infected patients after initiation of IFN-free direct-acting antiviral therapy. In Aim 3 we will use a mouse model of chronic viral infection (LCMV) to determine the effect of late blockade of IL-6 and IL-1β on the development of exhausted and senescent T cells, and the recovery of T cell function and proliferative ability. The candidate's long term goals are to understand the effects of chronic inflammation on health, the mechanisms by which the immune system maintains homeostasis, and how inflammation disrupts the ability of the immune system to reestablish homeostasis after infection and during aging. This focus supports a growing need nationwide to advance our understanding and develop therapeutic strategies in the aging veteran population with and without chronic viral infection. The candidate's career goals are to use this Career Development Award to successfully transition to an independent investigator at the Louis Stokes Cleveland VAMC, and to establish a productive, thriving, national leading research program in the VA system.