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

项目摘要/摘要这个名为“肺泡巨噬细胞池是HIV的储存库”的新提案解决了一个基本问题；特别是，当通过抗逆转录病毒治疗（ART）实现外周病毒抑制时，肺泡巨噬细胞池是否充当HIV的储存库？如果是这样，这个储存库如何改变肺泡空间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，即使他们坚持抗逆转录病毒治疗。我们有令人信服的实验证据表明，HIV感染抑制肺泡腔内的抗氧化防御并引起严重的氧化还原应激。基于本提案提供的初步数据，我们假设HIV抑制Nrf2的表达和作用，Nrf2是激活抗氧化反应元件（ARE）的主转录因子，部分原因是在这个脆弱的微环境中诱导锌缺乏。从而阻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，而这些抗氧化剂对于维持肺泡空间内健康的氧化还原电位至关重要。我们进一步假设，由于Nrf2-ARE信号通路的靶向抑制，

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.