Impact of smoking and its cessation on systemic and airway immune activation

项目摘要 吸烟率极高及其对艾滋病毒感染者发病率和死亡率的重大影响， 尽管抗逆转录病毒疗法有效，但由于吸烟对艾滋病毒感染人群的健康构成重大风险。 吸烟对艾滋病毒诱导的免疫功能障碍产生协同作用的机制仍然存在 不清楚我们的中心假设是，持续的艾滋病毒诱导的免疫功能障碍离开肺 非常容易受到吸烟的进一步侮辱。吸烟进一步驱动免疫介导的途径，如 氧化应激和炎症增加，导致进一步的局部组织破坏。肺部病理学可以 导致肺中潜伏感染的肺泡巨噬细胞活化，产生低水平的HIV病毒血症，和 使这种促炎环境得以延续。此外，慢性氧化失衡可能导致 仅局部组织损伤，但细胞DNA损伤，这导致上皮基因表达改变。目的 1试图在ART治疗的HIV吸烟者的横断面研究中确定吸烟的慢性免疫效应 通过评估细胞因子谱和免疫细胞表型以及细胞的ROS产生的差异， 从不吸烟的艾滋病毒感染者的呼吸道和血液中分离出来。这些地方和 气道上皮基因转录组的系统性免疫紊乱和残留病毒血症的证据将 评估以确定吸烟与HIV免疫功能障碍相互作用的生物学途径。在Aim中 2为了进一步验证这一假设，我们提出了一项概念验证戒烟临床研究，以评估 实现戒烟的HIV吸烟者肺损伤可逆性的程度和性质 与那些继续吸烟的人相比。在这项单中心研究中，我们将采用密集吸烟 一项戒烟计划，帮助从一家大型城市HIV感染者门诊招募的研究参与者 在一个独特的综合临床研究基础设施到位，实现戒烟。纵向 将在戒烟前和戒烟后从能够达到10周的患者中收集样本 从肺和血液停止。我们将评估炎症水平、免疫激活和 氧化应激，并确定这些免疫介导的途径是否与HIV残留量的变化有关。 病毒血症和肺上皮基因表达。最后，利用现有资源，我们将比较 与我们的合作者已经收集的库存样本中未感染吸烟者的结果相比。这 艾滋病病毒感染者戒烟研究将是第一次，纵向标本 从肺和血室收集，并利用平移方法， 与病毒学、免疫学、基因转录和健康差异研究方面的专家合作。 了解吸烟与免疫激活相互作用的相对贡献和途径， 慢性HIV疾病的炎症特征将有助于指导治疗干预措施的发展， 停止或逆转这些病理过程和随后的临床疾病。

PROJECT SUMMARY The exceedingly high rate of smoking and its substantial contribution to morbidity and mortality in the HIV- infected population despite effective ART makes smoking a major health risk in the HIV-infected population. The mechanism by which smoking exerts synergistic effects on HIV-induced immune dysfunction remains unclear. Our central hypothesis is that the persistent HIV-induced immune dysfunction leaves the lung exceeding vulnerable to further insults by smoking. Smoking further drives immune-mediate pathways, such as increase in oxidative stress and inflammation, to cause further local tissue destruction. The lung pathology can result in activation of latently infected alveolar macrophages in the lung to produce low level HIV viremia, and perpetuates this pro-inflammatory environment. Additionally, the chronic oxidative imbalance can cause not only local tissue damage but cellular DNA damage, which results in epithelial gene expression alterations. Aim 1 seeks to identify in a cross-sectional study of ART-treated HIV smokers chronic immune effects of smoking by evaluating for differences in cytokine profile and immune cell phenotype and ROS production of cells isolated in the airways and blood from HIV-infected never smokers. The relationships of these local and systemic immune perturbations with airway epithelial gene transcriptome and evidence of residual viremia will be evaluated to identify biological pathways by which smoking interacts with HIV immune dysfunction. In Aim 2 to further test the hypothesis we propose a proof-of-concept smoking cessation clinical study to assess the degree and nature of reversibility of lung damage among HIV smokers who achieve smoking cessation compared to those who continue to smoke. In this single site study, we will employ an intensive smoking cessation program to help study participants who are recruited from a large urban HIV-infected outpatient clinic where a unique integrated clinical research infrastructure is in place, achieve smoking cessation. Longitudinally samples will be collected pre-cessation and post-cessation from those who are able to achieve 10-week cessation from the lung and blood. We will evaluate the change in level of inflammation, immune activation and oxidative stress, and determine if these immune-mediate pathways are related to changes in HIV residual viremia and epithelial gene expression in the lung. Lastly, leveraging existing resources, we will compare these finding to those in uninfected smokers from banked samples collected already by our collaborator. This smoking cessation study in HIV-infected patients will be the first of its kind, with longitudinal specimen collection from both the lung and blood compartments, and utilizing translational approaches through collaborations with experts in virology, immunology, gene transcription and health disparity research. Understanding the relative contribution and pathways by which smoking interacts with immune activation and inflammation characteristic of chronic HIV disease will help guide development of therapeutic interventions to halt or reverse these pathological processes and ensuing clinical disease.