Immune enhancement for immunological non-responders to ART

描述（由申请人提供）：这项题为“免疫增强免疫无应答者对ART”的新提案详细介绍了一项新的临床试验，在感染人类免疫缺陷病毒（HIV）的个体中补充膳食锌和S-腺苷甲硫氨酸（SAMe），这些个体对抗逆转录病毒治疗（ART）没有充分反应。具体而言，大约35%的艾滋病毒感染者接受了适当剂量的抗逆转录病毒疗法治疗并实现了病毒学控制，但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之中，总体健康状况较差。这种高失败率的机制尚不清楚，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，这些因素在肺泡腔中特别成问题，它们损害肺泡巨噬细胞中的宿主免疫功能。具体而言，HIV感染或慢性酒精摄入的健康个体有氧化应激（如谷胱甘肽等巯基抗氧化剂的变化所反映），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。刺激性地，用锌和/或谷胱甘肽处理这些巨噬细胞提高了它们的吞噬能力。在实验模型中，我们已经确定，饮食补充锌和/或谷胱甘肽前体，如SAMe恢复健康的氧化还原状态和肺泡空间内的锌生物利用度，从而正常化肺泡巨噬细胞免疫功能。这些研究得到了其他临床证据的支持，这些证据表明，锌补充剂似乎可以减少HIV感染者免疫衰竭的进展，并且SAMe补充剂对HIV相关的抑郁症有有益的影响。综上所述，实验和临床证据有力地证明，锌和SAMe的组合将恢复免疫无应答者气道中的氧化还原和免疫健康，并且也可能具有有益的全身免疫作用。利用一个多学科的团队，包括埃默里大学和华盛顿大学艾滋病毒临床试验的临床研究人员， 华盛顿，翻译肺生物学科学家，和先进的代谢组学，基因组学和氧化还原生物化学研究平台，我们将评估肺特异性和全身反应，这种疗法。我们更大的目标是确定免疫无应答的新特征和/或机制，从而开发和测试可以增强ART效果并将“无应答者”转化为“应答者”的疗法。我们拥有一支独特的合格团队，专注于使用安全，简单，可行的有针对性的治疗方法来扩展和改善这些人的整体健康，无论是在我们的社会还是在医疗资源稀缺的社会中。 公共卫生相关性：这项名为“免疫增强对抗逆转录病毒疗法无反应者”的新项目将检验一种假设，即长期膳食补充锌和S-腺苷甲硫氨酸（SAMe）可以改善感染艾滋病毒和对抗逆转录病毒疗法没有充分反应的个人的整体肺部健康。大约35%的HIV感染者即使坚持抗逆转录病毒治疗也不能恢复正常的免疫功能，并且与获得免疫应答的个体相比，仍然处于肺部感染、慢性肺部疾病以及总体发病率和死亡率增加的高风险中。虽然这种高失败率的机制尚不清楚，但我们从实验和临床研究中获得了广泛的经验证据，表明锌缺乏和氧化应激在糖尿病患者中起着重要作用。 呼吸道起着重要的作用，长期膳食补充锌和SAMe可以改善免疫反应和整体肺部健康。

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.