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.

慢性全身炎症与老年人的免疫功能障碍和发病有关，接受治疗 HIV感染和HCV感染。我们认为循环炎症蛋白会导致免疫衰竭 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（HCV），感染HCV的美国退伍军人的平均年龄是 已近65岁。尽管新的无干扰素直接作用抗病毒疗法在清除病毒方面非常有效 从患者身上，患者留下了数十年感染和肝损伤的后果，这是 仍不清楚可溶性炎症介质持续多久，以及免疫功能障碍和 相关的发病率持续存在。同样，即使是已成功控制病毒的艾滋病毒感染者 几十年来 ART 的复制增加了死亡率和发病率以及持续性炎症。弗吉尼亚州 是美国最大的艾滋病毒护理单一提供者。了解导致持续发病的原因 这些经验丰富的患者群体至关重要。老年人、HCV和HIV感染者都患有慢性病 免疫炎症和这三个患者组有许多相同的合并症，包括 心血管疾病、癌症和肝脏疾病。该 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的血浆长期升高 IL-6 水平，以及我们最新的数据表明 HIV 感染者淋巴结中 IL-1β 水平升高 患者。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，并检查潜在的治疗方法 慢性感染期间暂时阻断IL-6和IL-1β对改善免疫功能和恢复的作用 耗尽或衰老的 T 细胞。假设衰老过程中 IL-6 和 IL-1β 水平长期升高， HCV 感染和 HIV 感染会导致免疫衰老和衰竭，从而导致免疫 功能障碍将在 3 个特定目标中进行测试。目标 1 将确定 T 细胞的表型和功能 通过对衰竭或衰老标记物呈阳性的细胞进行分选，在体外暴露于 IL-1β 或 IL-6 （PD-1、CD57、Tim-3、KLRG1、Lag3）并检查它们的功能能力以确定是否存在炎症 细胞因子本身就可以驱动衰老，与抗原暴露无关。目标 2A 将检查表达式 疲劳和衰老标志物的水平以及与细胞因子相关的细胞内产生 HCV 感染、HIV 感染治疗的淋巴细胞中的衰老相关分泌表型 (SASP) 和老年患者通过流式细胞术。目标 2B 将检查免疫的恢复和正常化 纵向功能，在开始 ART 后的 HIV 感染患者和在开始 ART 后的 HCV 感染患者中 开始无干扰素直接作用抗病毒治疗。在目标 3 中，我们将使用慢性病毒感染小鼠模型 感染（LCMV）以确定后期阻断 IL-6 和 IL-1β 对衰竭发展的影响 和衰老的T细胞，以及T细胞功能和增殖能力的恢复。候选人的长期 目标是了解慢性炎症对健康的影响、免疫系统的机制 系统维持体内平衡，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稳态。这一重点支持全国范围内不断增长的需求，以推进我们的 了解并制定患有或不患有慢性病毒的老年退伍军人群体的治疗策略 感染。候选人的职业目标是利用此职业发展奖成功过渡到 路易斯·斯托克斯克利夫兰 VAMC 的独立调查员，并建立一个富有成效、蓬勃发展、 VA 系统的国家领先研究计划。