HIV-induced redox stress and the alveolar macrophage as a resistant reservoir

HIV 诱导的氧化还原应激和肺泡巨噬细胞作为耐药库

基本信息

批准号：
8790508
负责人：
Lou Ann S Brown
金额：
$ 68.77万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-06 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8790508
关键词：
Acquired Immunodeficiency Syndrome Acute Acute Lung Injury Address Adjuvant Therapy Alveolar Alveolar Macrophages Anti-Retroviral Agents Antioxidants Ants Biological Availability Blood CD4 Lymphocyte Count CD4 Positive T Lymphocytes Cause of Death Cell Count Chronic Chronic lung disease Clinical Clinical Investigator Clinical Research Clinical Trials Data Development Diet Dietary Zinc Disease Enrollment Environment Epithelial Equilibrium Experimental Models Foundations Genes Glutathione HIV HIV-1 Health Highly Active Antiretroviral Therapy Human Immune Immune System Diseases Immune response Immunity Individual Infection Life Liquid substance Lung Macrophage Activation Morbidity - disease rate National Heart, Lung, and Blood Institute Normal Range Outcome Oxidants Oxidation-Reduction Oxidative Stress Peripheral Persons Phenotype Pneumonia Population Pre-Clinical Model Premature Mortality Proteins Pulmonary Emphysema Rattus Resistance Response Elements Risk S-Adenosylmethionine Signal Pathway Signal Transduction Stress Sulfhydryl Compounds Supplementation Techniques Testing Therapeutic Time Transgenic Organisms Translating Viral Viral Load result Virus Virus Diseases Virus Replication Zinc Zinc Fingers Zinc deficiency activating transcription factor alveolar epithelium base clinically relevant cohort design disability immune function improved indexing innate immune function insight macrophage meetings metabolomics monocyte novel outcome forecast pathogen prevent prospective public health relevance research study response transcription factor virus pathogenesis

项目摘要

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT This new proposal entitled "The alveolar macrophage pool is a reservoir of HIV" addresses a fundamental question; specifically, does the alveolar macrophage pool serve as a reservoir of HIV even when peripheral viral suppression is achieved by anti-retroviral therapy (ART) and if so, how does this reservoir alter the environment within the alveolar space and impair alveolar macrophage immune function? This is a critical question to address as lung infections remain the leading cause of death in persons living with HIV even when they are adherent to ART. We have compelling experimental evidence that HIV infection inhibits anti-oxidant defenses within the alveolar space and causes severe redox stress. Based on preliminary data presented in this proposal, we hypothesize that HIV inhibits the expression and actions of Nrf2, the master transcription factor that activates the anti-oxidant response element (ARE), in part by inducing zinc deficiency in this vulnerable microenvironment, and thereby prevents the alveolar epithelium and the alveolar macrophage from generating glutathione and other anti-oxidants that are critically required to maintain a healthy redox potential within the alveolar space. We further hypothesize that as a result of this targeted inhibition of the Nrf2-ARE signaling pathway, HIV promotes its own ability to infect alveolar macrophages and accumulate a large pool of intracellular pro-virus that produces a large HIV reservoir within the alveolar space. In parallel, HIV-induced oxidative stress shifts the alveolar macrophage toward alternative activation (so called 'M2 phenotype'). As a consequence, the innate immune capacity of the alveolar macrophage is impaired and this not only confers further resistance to clearing the viral reservoir but also renders the infected individual susceptible to serious lung infections. Our collaborative team of basic and clinical investigators will leverage our ongoing collaborative clinical studies in HIV-infected individuals. As a result, we not only have ongoing access to alveolar epithelial lining fluid and macrophages from well-defined subsets of HIV-infected individuals, we also have the expertise to apply state-of-the-art basic techniques in HIV pathogenesis, metabolomics, and redox signaling to test our hypotheses. In parallel, we are already conducting a prospective clinical trial of dietary zinc and S-adenosylmethionine (a thiol anti-oxidant that among its many actions increases the glutathione pool in the alveolar space) in HIV-infected individuals with inadequate immunological responses to ART. This unique cohort will form the foundation for a greatly expanded clinical trial that will enable us to test the corollary hypothesis that therapeutic strategies designed to improve zinc bioavailability and the redox potential within the alveolar space can enhance alveolar macrophage innate immune function and significantly decrease the HIV reservoir in the lung. This project will produce novel insights into how we can target the alveolar macrophage pool to decrease HIV burden as well as improve lung health in these vulnerable individuals.

描述（由申请人提供）：项目摘要/摘要这项题为“肺泡巨噬细胞库是 HIV 的储存库”的新提案解决了一个基本问题；具体来说，即使通过抗逆转录病毒治疗（ART）实现了外周病毒抑制，肺泡巨噬细胞池是否仍可充当 HIV 储存库？如果是，该储存库如何改变肺泡腔内的环境并损害肺泡巨噬细胞的免疫功能？这是一个需要解决的关键问题，因为肺部感染仍然是艾滋病毒感染者死亡的主要原因，即使他们坚持接受抗逆转录病毒治疗。我们有令人信服的实验证据表明，艾滋病毒感染会抑制肺泡腔内的抗氧化防御，并导致严重的氧化还原应激。根据本提案中提供的初步数据，我们假设 HIV 抑制 Nrf2（激活抗氧化反应元件 (ARE) 的主转录因子）的表达和作用，部分是通过在这个脆弱的微环境中诱导锌缺乏，从而抑制 Nrf2 的表达和作用。防止肺泡上皮和肺泡巨噬细胞产生谷胱甘肽和其他抗氧化剂，而这些抗氧化剂是维持肺泡腔内健康氧化还原电位所必需的。我们进一步假设，由于 Nrf2-ARE 信号通路的这种靶向抑制， HIV 增强自身感染肺泡巨噬细胞的能力，并积累大量细胞内前病毒，从而在肺泡腔内产生大量 HIV 病毒库。并联， HIV 诱导的氧化应激使肺泡巨噬细胞转向替代激活（所谓的“M2 表型”）。结果，肺泡巨噬细胞的先天免疫能力受损，这不仅进一步抵抗清除病毒库，而且使感染者容易遭受严重的肺部感染。我们的基础和临床研究人员合作团队将利用我们正在进行的针对艾滋病毒感染者的合作临床研究。因此，我们不仅能够持续获得来自明确的 HIV 感染者亚群的肺泡上皮内衬液和巨噬细胞，而且我们还拥有在 HIV 发病机制、代谢组学、和氧化还原信号来测试我们的假设。与此同时，我们已经在对 ART 免疫反应不足的 HIV 感染者中开展一项前瞻性临床试验，使用膳食锌和 S-腺苷甲硫氨酸（一种硫醇抗氧化剂，其多种作用可增加肺泡腔中的谷胱甘肽库）。这个独特的队列将为大幅扩展的临床试验奠定基础，使我们能够测试推论假设，即旨在提高锌生物利用度和肺泡腔内氧化还原电位的治疗策略可以增强肺泡巨噬细胞先天免疫功能并显着降低 HIV 感染肺部的水库。该项目将为我们如何针对肺泡巨噬细胞库来减少艾滋病毒负担并改善这些易感人群的肺部健康提供新的见解。