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

描述(由申请人提供)：酒精滥用会降低抗逆转录病毒治疗的依从性，增加肺孢子虫(PCP)等机会性感染，从而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强大的先天免疫反应以及完整的肺泡上皮屏障来限制肺损伤，这两者都会因酗酒而受损。重要的是，并不是HIV-1感染的所有表现都可以归因于病毒感染本身，有证据表明，包括gp120和Tat在内的HIV-1相关蛋白可以诱导氧化应激，并直接损害靶组织。参与这项研究的研究人员发现，长期摄入乙醇还会导致肺泡腔内严重的、以前未被认识到的氧化应激，导致肺泡上皮和肺泡巨噬细胞功能障碍。同时(或可能作为结果)，酒精摄入损害了肺泡上皮细胞和巨噬细胞的粒细胞/巨噬细胞集落刺激因子(GM-CSF)受体的表达和信号，重组GM-CSF恢复了酒精喂养大鼠肺泡上皮细胞和巨噬细胞的功能。值得注意的是，这些氧化应激和GM-CSF信号的异常也存在于HIV-1转基因大鼠中，并因长期摄入酒精而加剧。为这一探索性R21建议奠定基础的新的初步研究表明，HIV-1相关蛋白和慢性乙醇摄入可能通过不同的机制深刻地损害肺泡腔内的GM-CSF信号，这对HIV-1感染者的肺宿主防御具有巨大的影响，特别是在酒精滥用的背景下。本项目将在相关动物模型中研究慢性酒精摄入与HIV-1相关蛋白在肺泡上皮和巨噬细胞内GM-CSF信号和GM-CSF依赖功能上的表达的相互作用，以及这如何影响体内PCP从肺中的清除。同时，将测试包括原半胱氨酸(一种抗氧化剂)和重组GM-CSF在内的新型辅助疗法，以确定即使在慢性HIV-1相关蛋白表达/酒精摄入的情况下，肺泡上皮和巨噬细胞功能是否可以得到改善。最终，该项目的长期目标是确定有效的新辅助疗法，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.