Immune enhancement for immunological non-responders to ART

ART 免疫无反应者的免疫增强

• 批准号: 8551693
• 负责人: David Marshall Guidot
• 金额: $ 44.59万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8551693
• 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.

描述（由申请人提供）：这个名为“增强抗逆转录病毒治疗免疫无应答者的免疫”的新提案详细介绍了一项新的临床试验，该试验在对抗逆转录病毒治疗（ART）没有充分反应的人类免疫缺陷病毒（HIV）感染者中补充膳食锌和s -腺苷蛋氨酸（SAMe）。具体而言，在接受适当剂量抗逆转录病毒药物治疗并实现病毒学控制的艾滋病毒感染者中，约35%的人没有恢复健康的免疫反应，仍然处于肺部感染和慢性肺部疾病的高风险中，总体健康结果更差。这种高失败率背后的机制尚不清楚，但年龄较大和长期饮酒与免疫无反应性风险增加有关。HIV感染与锌缺乏和氧化应激有关，我们有令人信服的实验和临床证据表明，这些因素在肺泡间隙尤其成问题，因为它们损害肺泡巨噬细胞的宿主免疫功能。具体来说，感染HIV或长期饮酒的健康个体有氧化应激（如硫醇抗氧化剂如谷胱甘肽的变化）、锌缺乏和肺泡巨噬细胞摄取和杀死细菌的能力受损的证据。刺激的是，用锌和/或谷胱甘肽治疗这些巨噬细胞可以提高它们的吞噬能力。在实验模型中，我们已经确定，在饮食中补充锌和谷胱甘肽前体（如SAMe）可恢复肺泡空间内健康的氧化还原状态和锌的生物利用度，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，锌补充剂似乎可以减少艾滋病毒感染者免疫功能衰竭的进展，并且SAMe补充剂对艾滋病毒相关抑郁症有有益作用。综上所述，实验和临床证据有力地表明，锌和SAMe的组合将恢复免疫无应答者气道的氧化还原和免疫健康，并可能具有有益的全身免疫作用。利用一个多学科团队，其中包括埃默里大学（Emory University）和华盛顿大学（University of the University）艾滋病临床试验的知名临床研究人员