HIV-1 and ethanol-induced alveolar epithelial and macrophage dysfunction

描述（由申请人提供）：酒精滥用通过降低抗逆转录病毒治疗的依从性和增加肺孢子虫（PCP）等机会性感染，加剧人类免疫缺陷病毒1型（HIV-1）感染。宿主对PCP和其他病原体的防御需要肺泡巨噬细胞的强大先天免疫应答以及完整的肺泡上皮屏障来限制肺损伤，这两者都受到酒精滥用的损害。重要的是，并非HIV-1感染的所有表现都可归因于病毒感染本身，有证据表明，包括gp 120和达特在内的HIV-1相关蛋白可诱导氧化应激并直接损伤靶组织。研究人员在这项提案中已经确定，慢性乙醇摄入也会导致严重的和以前未被认识到的肺泡腔内的氧化应激，导致肺泡上皮细胞和肺泡巨噬细胞功能障碍。与此同时（或可能因此），乙醇摄入损害肺泡上皮细胞和巨噬细胞中粒细胞/巨噬细胞集落刺激因子（GM-CSF）受体的表达和信号传导，重组GM-CSF恢复乙醇喂养大鼠的肺泡上皮细胞和巨噬细胞功能。值得注意的是，这些氧化应激和GM-CSF信号传导的异常也存在于HIV-1转基因大鼠中，并因慢性乙醇摄入而加剧。新的初步研究为这项探索性的R21建议奠定了基础，表明HIV-1相关蛋白和慢性乙醇摄入可能通过不同的机制发挥作用，深刻损害肺泡间隙内的GM-CSF信号传导，这对HIV-1感染者的肺部宿主防御具有巨大的影响，特别是在酒精滥用的情况下。该项目将研究慢性乙醇摄入和HIV-1相关蛋白表达对肺泡上皮细胞和巨噬细胞内GM-CSF信号传导和GM-CSF依赖性功能之间的相互作用，以及这如何影响PCP在相关动物模型中体内从肺中的清除。与此同时，将测试包括原半胱氨酸（一种抗氧化剂）和重组GM-CSF在内的新型抗氧化疗法，以确定即使在慢性HIV-1相关蛋白表达+/-乙醇摄入的情况下，肺泡上皮和巨噬细胞功能是否也能得到改善。最终，该项目的长期目标是确定有效的新的预防性疗法，可以补充标准治疗并增强HIV-1感染者的肺功能。

DESCRIPTION (provided by applicant): Alcohol abuse exacerbates human immunodeficiency virus type 1 (HIV-1) infection by decreasing compliance with anti-retroviral therapy and increasing opportunistic infections such as pneumocystis (PCP). Host defense against PCP and other pathogens requires robust innate immune responses by alveolar macrophages as well as an intact alveolar epithelial barrier to limit lung injury, both of which are impaired by alcohol abuse. Importantly, not all manifestations of HIV-1 infection can be attributed to viral infection itself, and there is evidence that HIV-1-related proteins including gp120 and Tat can induce oxidative stress and directly damage target tissues. Investigators in this proposal have identified that chronic ethanol ingestion also causes severe and previously unrecognized oxidative stress within the alveolar space, leading to alveolar epithelial and alveolar macrophage dysfunction. In parallel (or perhaps as a consequence) ethanol ingestion impairs granulocyte/macrophage colony-stimulating factor (GM-CSF) receptor expression and signaling in alveolar epithelial cells and macrophages, and recombinant GM-CSF restores alveolar epithelial cell and macrophage function in ethanol-fed rats. Remarkably, these abnormalities in oxidative stress and GM-CSF signaling are also present in HIV-1 transgenic rats and are exacerbated by chronic ethanol ingestion. New preliminary studies that form the foundation for this exploratory R21 proposal suggest that HIV-1-related proteins and chronic ethanol ingestion may act via different mechanisms to profoundly impair GM-CSF signaling within the alveolar space, which has enormous implications for pulmonary host defense in HIV-1-infected individuals, particularly in the context of alcohol abuse. This project will study the interactions between chronic ethanol ingestion and HIV-1-related protein expression on GM-CSF signaling and GM-CSF- dependent functions within the alveolar epithelium and macrophage, and how this affects clearance of PCP from the lung in vivo, in a relevant animal model. In parallel, novel adjunctive therapies including procysteine (an antioxidant) and recombinant GM-CSF will be tested to determine if alveolar epithelial and macrophage function can be improved even in the face of chronic HIV-1-related protein expression +/- ethanol ingestion. Ultimately, the long-term goal of this project is to identify effective new adjunctive therapies that can complement standard treatment and enhance lung function in HIV-1-infected individuals.