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

IL-6 和 IL-1b 在衰老、HIV 和 HCV 感染期间免疫功能障碍中的作用

• 批准号: 9858239
• 负责人: Carey Lynn Shive
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9858239
• 关键词: Activities of Daily Living; Age; Aging; American; Antigens; Antiviral Therapy; Cardiovascular Diseases; Caring; Cell Aging; Cell Culture Techniques; Cell Proliferation; Cell Separation; Cell physiology; Cells; Chronic; Chronic Hepatitis C; Cultured Cells; Data; Development; Elderly; Excision; Exposure to; Flow Cytometry; Functional disorder; Goals; HIV; HIV Infections; HIV/HCV; Health; Hepatitis C; Hepatitis C virus; Homeostasis; Human; IL6 gene; IL7 gene; Immune; Immune System Diseases; Immune system; Immunologic Markers; In Vitro; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory; Interferons; Interleukin-1 beta; Interleukin-6; K-Series Research Career Programs; Late Effects; Left; Liver diseases; Lymphocytic choriomeningitis virus; Malignant Neoplasms; Measures; Morbidity - disease rate; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Population; Production; Proliferating; Proteins; Provider; Recovery; Research; Research Personnel; Rheumatoid Arthritis; Role; System; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Up-Regulation; Veterans; Viral; Virus; Virus Diseases; Virus Replication; aged; antiretroviral therapy; base; career; chronic infection; comorbidity; cytokine; design; exhaust; exhaustion; human old age (65+); immune function; immune health; improved; insight; liver injury; lymph nodes; military veteran; mortality; mouse model; novel strategies; older patient; patient population; programmed cell death protein 1; programs; response; senescence; systemic inflammatory response; targeted treatment; therapeutic target

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.

慢性全身性炎症与经常治疗的免疫功能障碍和病态有关 HIV感染和HCV感染。我们建议循环炎性蛋白驱动免疫疲劳 感受并导致这些患者组中看到的免疫功能障碍。将近400万 美国人感染了丙型肝炎病毒（HCV），而感染HCV的美国退伍军人的平均年龄为 接近65年。尽管新的无IFN直接作用抗病毒疗法在清除病毒方面非常有效 从患者那里，患者留下了数十年感染和肝损害的后果，这是 尚不清楚炎症的固体介质持续多长时间，以及免疫功能障碍和 相关的发病率持续。同样，即使感染了成功控制病毒的HIV感染患者 数十年来，用艺术复制增加了死亡率，发病率和持续性炎症。 VA 是美国最大的艾滋病毒护理单一提供商。了解什么导致持续发病 这些老将患者人数至关重要。较早的HCV和HIV感染患者都有慢性 免疫炎症和这三个患者组共享许多相同的合并症 心血管疾病，癌症和肝病。此CDA-2应用程序的项目设计基于 了解患有慢性病毒感染和老年患者的患者表现出慢性血浆 IL-6的水平和我们最近的数据表明，HIV感染的淋巴结中IL-1β水平升高 患者。这项研究的核心目标是确定IL-6和IL-1β的基本机制 有助于免疫疲劳和感应的发展，并检查潜在的治疗 在慢性感染过程中暂时阻断IL-6和IL-1β的作用，以提高免疫功能和恢复 疲惫或感觉T细胞。慢性在衰老过程中慢性IL-6和IL-1β水平升高的假设， HCV感染和HIV感染有助于免疫衰竭和衰竭以及由此产生的免疫 功能障碍将以3个特定目的进行测试。 AIM 1将确定T细胞的表型和功能 通过对细胞的疲惫或感觉标记呈阳性，在体外暴露于IL-1β或IL-6 （PD-1，CD57，TIM-3，KLRG1，LAG3）并检查其功能能力以确定是否炎症 仅细胞因子就可以吸引感应，而与抗原暴露无关。 AIM 2A将检查表达 疲惫和感觉标记的水平以及与该细胞因子的细胞内产生 来自HCV感染的，经过治疗的HIV感染的淋巴细胞中的感应相关秘书表型（SASP）， 以及通过流式细胞术的老患者。 AIM 2B将检查免疫的恢复和归一化 在ART主动和HCV感染的患者之后，在纵向的HIV感染患者中的功能 启动无IFN直接作用抗病毒疗法。在AIM 3中，我们将使用慢性病毒的小鼠模型 感染（LCMV）确定IL-6和IL-1β的后期封锁对耗尽的影响 和感觉T细胞，以及T细胞功能的恢复和增殖能力。候选人的长期 目标是了解慢性感染对健康的影响，即免疫的机制 系统保持体内平衡，以及炎症如何破坏免疫系统重新建立的能力 感染后和衰老期间的稳态。这种重点支持全国增长的需求，以促进我们的 理解和发展具有和没有慢性病毒的老年退伍军人人口的理论策略 感染。候选人的职业目标是使用该职业发展奖，以成功地过渡到 路易斯·斯托克斯·克利夫兰VAMC的独立调查员，建立一个富有成效的繁荣， VA系统中的国家领先研究计划。