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

• 批准号: 9100906
• 负责人: Lou Ann S Brown
• 金额: $ 66.37万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 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/9100906
• 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; Techniques; Testing; Therapeutic; Time; Transgenic Organisms; Translating; Viral; Viral Load result; Viral reservoir; Virus; Virus Diseases; Virus Replication; Zinc; Zinc Fingers; Zinc deficiency; Zinc supplementation; 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

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/摘要这个新提案，标题为“肺泡巨噬细胞池是艾滋病毒的储层”，解决了一个基本问题；具体而言，肺泡巨噬细胞池即使通过抗逆转录病毒疗法（ART）实现周围病毒抑制（ART），并且该储层如何改变肺泡空间内的环境并损害肺泡巨噬细胞免疫功能？这是一个关键的问题，因为肺部感染仍然是艾滋病毒感染者的主要死亡原因，即使他们遵守艺术。我们有令人信服的实验证据，表明艾滋病毒感染抑制肺泡空间内的抗氧化剂防御，并引起严重的氧化还原应激。 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至关重要的是要在肺泡空间内保持健康的氧化还原电位。我们进一步假设，由于这种靶向抑制NRF2-ARE信号通路， HIV促进其自身感染肺泡巨噬细胞的能力，并积累大量的细胞内预病毒，该病毒在肺泡空间内产生大型HIV储量。并联， HIV诱导的氧化应激将肺泡巨噬细胞转移到替代激活（所谓的“ M2表型”）。结果，肺泡巨噬细胞的先天免疫能力受到损害，这不仅赋予了清除病毒储量的进一步抵抗力，而且还使受感染的人易受严重的肺部感染。我们的基础和临床研究人员的合作团队将利用我们在受艾滋病毒感染者中正在进行的合作临床研究。结果，我们不仅可以持续进入肺泡上皮衬里的液体和来自艾滋病毒感染的个体的明确定义子集的巨噬细胞，而且我们还具有专业知识，可以在HIV发病机理，代谢组学和REDOX信号中应用最新的基本技术来测试我们的假设。同时，我们已经在对艾滋病毒感染的患者中的饮食锌和S-腺苷硫氨酸（一种硫醇抗氧化剂）进行了前瞻性临床试验（一种硫醇抗氧化剂）在HIV感染的个体中增加了对ART免疫学反应不足的人的谷胱甘肽池。这个独特的队列将为大大扩展的临床试验奠定基础，这将使我们能够测试旨在提高锌生物利用度和肺泡空间内的氧化还原电位的治疗策略，可以增强肺泡巨噬细胞的先天免疫功能，并显着降低肺中的HIV Reserereser。该项目将对我们如何瞄准肺泡巨噬细胞池以减轻艾滋病毒负担并改善这些弱势群体的肺部健康，从而产生新的见解。