Immune enhancement for immunological non-responders to ART

ART 免疫无反应者的免疫增强

• 批准号: 8445018
• 负责人: David Marshall Guidot
• 金额: $ 47.56万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445018
• 关键词: Acquired Immunodeficiency Syndrome; Address; Age; Alcohol consumption; Alveolar; Alveolar Macrophages; Anti-Retroviral Agents; Antioxidants; Bacteria; Biochemistry; Biological Availability; Biology; Bronchoalveolar Lavage; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cell Count; Chronic; Chronic lung disease; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Development; Dietary Supplementation; Dietary Zinc; Disease; Dose; Equilibrium; Exhalation; Experimental Models; Failure; Genomics; Glutathione; Goals; HIV; HIV-1; Health; Healthcare; Highly Active Antiretroviral Therapy; Immune; Immune response; Immunity; Incidence; Individual; Infection; Lung; Measurement; Mental Depression; Monitor; Morbidity - disease rate; Natural Immunity; Outcome; Oxidation-Reduction; Oxidative Stress; Peripheral; Play; Pneumonia; Predisposition; Proteins; Qualifying; Research; Resources; Risk; Risk Factors; Role; S-Adenosylmethionine; Scientist; Severities; Societies; Staging; Sulfhydryl Compounds; Supplementation; Techniques; Testing; Translating; Treatment Efficacy; Universities; Viral; Virus Diseases; Vulnerable Populations; Washington; Zinc; Zinc deficiency; chronic alcohol ingestion; cohort; efficacy testing; high risk; immune function; improved; innate immune function; killings; macrophage; metabolomics; mortality; multidisciplinary; novel; outcome forecast; research study; response; restoration; therapeutic target

DESCRIPTION (provided by applicant): This new proposal entitled "Immune enhancement for immunological non-responders to ART" details a novel clinical trial of dietary zinc and S-adenosylmethionine (SAMe) supplementation in individuals infected with the human immunodeficiency virus (HIV) who do not respond adequately to anti-retroviral therapy (ART). Specifically, approximately 35% of HIV-infected individuals who are treated with appropriate doses of ART and achieve virological control nevertheless do not recover a healthy immune response and remain at high risk for lung infections and chronic lung diseases, and have worse overall health outcomes. The mechanisms underlying this high failure rate are unknown, but older age and chronic alcohol use are associated with increased risk of immunological non-responsiveness. HIV infection is associated with zinc deficiency and oxidative stress, and we have compelling experimental and clinical evidence that these factors are particularly problematic in the alveolar space where they impair host immune functions in the alveolar macrophage. Specifically, otherwise healthy individuals with HIV infection or chronic alcohol ingestion have evidence of oxidative stress (as reflected by changes in thiol anti-oxidants such as glutathione), zinc deficiency, and impaired alveolar macrophage capacity to ingest and kill bacteria. Provocatively, treating these macrophages with zinc and/or glutathione improves their phagocytic capacity. In experimental models we have determined that dietary supplementation with zinc and/or glutathione precursors such as SAMe restore a healthy redox state and zinc bioavailability within the alveolar space and thereby normalize alveolar macrophage immune function. These studies are supported by other clinical evidence that zinc supplementation appears to decrease the progression of immune failure in HIV-infected individuals, and that SAMe supplementation has salutary effects on HIV-related depression. Taken together, the experimental and clinical evidence strongly argues that a combination of zinc and SAMe will restore redox and immune health in the airways of immunological non-responders, and could have salutary systemic immune effects as well. Using a multidisciplinary team that includes established clinical investigators in HIV clinical trials at Emory University and the University of Washington, translational lung biology scientists, and sophisticated state-of-the-art research platforms in metabolomics, genomics, and redox biochemistry, we will assess both the lung-specific and the systemic responses to this therapy. Our larger goal is to identify novel features and/or mechanisms underlying immunological non-responsiveness and thereby develop and test therapies that can enhance the effects of ART and convert 'non-responders' to 'responders'. We have a uniquely qualified team that is focused on extending and improving the overall health of these individuals using targeted therapeutic approaches that are safe, simple, and feasible for broad delivery both in our society as well as in societies where healthcare resources are much scarcer. PUBLIC HEALTH RELEVANCE: This new project entitled "Immune enhancement for immunological non-responders to ART" will test the hypothesis that long-term dietary supplementation with zinc and S-adenosylmethionine (SAMe) can improve the overall lung health of individuals who are infected with HIV and who do not respond adequately to anti- retroviral therapy. Approximately 35% of HIV-infected individuals do not recover their normal immune function even if they are adherent with anti-retroviral therapy and remain at high risk for pulmonary infections, chronic lung disease, and increased overall morbidity and mortality compared to individuals who achieve an immunological response. Although the mechanisms underlying this high failure rate are unknown, we have extensive empiric evidence from experimental and clinical studies that suggest that zinc deficiency and oxidative stress within the airways play important roles, and that long-term dietary supplementation with zinc and SAMe can improve immune responses and overall lung health.

描述（由申请人提供）：这一新提案为“免疫学非反应者的免疫增强艺术”详细介绍了对感染人类免疫缺陷病毒（HIV）感染的个体的饮食锌和S-腺苷硫氨酸（相同）补充的新型临床试验，这些病毒（HIV）对抗逆转录病毒的反应不当。具体而言，通过适当剂量的ART治疗并获得病毒学控制的艾滋病毒感染的个体中，大约有35％的人不会恢复健康的免疫反应，并且仍处于肺部感染和慢性肺部疾病的高风险，并且总体健康状况较差。该高失败率的基础机制尚不清楚，但是年龄较大和慢性饮酒与免疫无反应性的风险增加有关。 HIV感染与锌缺乏症和氧化应激有关，我们有令人信服的实验和临床证据，表明这些因素在肺泡空间中尤其有问题，在肺泡空间中，它们会损害肺泡巨噬细胞中的宿主免疫功能。具体而言，否则健康的艾滋病毒感染或慢性酒精摄入的健康个体具有氧化应激的证据（如硫醇抗氧化剂（如谷胱甘肽）的变化所反映的），锌缺乏症以及肺泡巨噬细胞能力受损而摄入并杀死细菌。挑衅地，用锌和/或谷胱甘肽治疗这些巨噬细胞可提高其吞噬能力。在实验模型中，我们确定饮食补充锌和/或谷胱甘肽前体（例如同一恢复肺泡空间内健康的氧化还原状态和锌生物利用度），从而使肺泡巨噬细胞免疫功能正常化。这些研究得到了其他临床证据的支持，表明补充锌似乎会降低HIV感染的个体免疫失败的进展，并且这种补充对与HIV相关的抑郁症具有巨大影响。综上所述，实验和临床证据强烈认为，锌和锌的组合将恢复免疫非应答者气道中的氧化还原和免疫健康，并且也可能具有伟大的全身免疫效应。使用一个多学科团队，其中包括埃默里大学和大学的HIV临床试验中既定的临床研究者 华盛顿，转化肺生物学科学家以及代谢组学，基因组学和氧化还原生物化学方面的先进最先进的研究平台，我们将评估肺特异性和对这种疗法的全身反应。我们的更大目标是确定免疫无反应性的新型特征和/或机制，从而开发和测试可以增强艺术作用并将“非反应者”转换为“反应者”的效果的疗法。我们有一个独特的团队，专注于使用有针对性的治疗方法来扩展和改善这些人的整体健康，这些方法是安全，简单且可行的，可在我们的社会以及医疗资源稀缺的社会中进行广泛交付。 公共卫生相关性：这个题为“免疫无反应者的免疫增强艺术的免疫力”将检验以下假设：长期饮食补充锌和S-腺苷甲氨酸（同一）可以改善受HIV感染和对抗逆转录病毒疗法反应不当的人的整体肺健康。与获得免疫学反应的人相比，HIV感染者中约有35％的人也不会恢复其正常免疫功能，即使他们遵守抗返回病毒疗法，并且仍然处于肺部感染，慢性肺部疾病和总体发病率和死亡率的高风险。尽管该高失败率的基础机制尚不清楚，但我们从实验和临床研究中获得了广泛的经验证据，这些证据表明锌缺乏症和氧化应激 航空公司起着重要作用，长期用锌及其饮食补充可以改善免疫反应和整体肺部健康。