Interactions of smoking, PD-1 and IL-10 in HIV-associated lung disease

描述（由申请人提供）：肺被认为是人类免疫缺陷病毒1型（HIV-1）感染的感染性和非感染性并发症的主要靶点之一。尽管开始了抗逆转录病毒治疗（ART），肺部并发症 HIV-1/AIDS的流行仍然是HIV-1感染患者发病和死亡的主要原因，细菌性肺炎和慢性阻塞性肺病（COPD）是最常见的肺部疾病。在肺炎之后，这些个体经历肺功能的下降，这在未感染HIV-1的人群中没有观察到，并且HIV-1感染的吸烟者的子集发展为肺气肿的加速形式。然而，HIV-1感染者肺炎和COPD风险增加的潜在机制尚不清楚。在这方面，吸烟和COPD与肺泡巨噬细胞朝向与免疫调节相关的免疫表型的重编程相关。在HIV-1感染的受试者中，血液和支气管肺泡灌洗液（BAL）中抗炎细胞因子IL-10的表达增加。我们的初步数据显示，与未感染的个体相比，HIV-1感染的吸烟者和非吸烟者的肺泡巨噬细胞（AM）分泌更多的IL-10来响应脂多糖（LPS），并且香烟烟雾暴露减少了LPS诱导的AM分泌TNF-α。重要的是，已经观察到HIV-1感染受试者中血液单核细胞上共抑制受体程序性死亡1（PD-1）的表达增加与IL-10分泌之间的联系。PD-1在慢性抗原暴露的情况下在T细胞上上调，导致T细胞功能障碍和无法清除HIV-1。我们的初步数据进一步表明，与血液中的T细胞相比，肺中的HIV-1特异性CD 4+和CD 8 + T细胞具有PD-1的上调表达，导致功能失调的T细胞表型。基于这些发现，我们假设AM分泌IL-10增加的免疫调节结果、功能失调的T细胞表型和HIV-1诱导的免疫抑制联合收割机联合使HIV-1感染的肺易于感染和损伤，从而加速HIV-1感染的吸烟者COPD的发展。使用来自吸烟者和非吸烟者的血液和BAL细胞，有和没有HIV-1感染，我们将确定HIV-1和吸烟对AM的PD-1表达和IL-10产生的影响。第二个目标是评估AM上PD-1和IL-10表达之间的关系及其对ART前后肺中T细胞功能的影响。在具体目标3中，我们将使用病例对照研究来评估AM和T细胞功能与肺功能和COPD发展的生理指标之间的关系。这些研究将促进我们对吸烟对HIV- 1感染肺部先天免疫和适应性免疫的影响以及这些反应与慢性肺部疾病发展的关系的理解。

DESCRIPTION (provided by applicant): The lung has been recognized as one of the main targets of infectious and non-infectious complications of human immunodeficiency virus type 1 (HIV-1) infection. Despite the initiation of anti-retroviral therapy (ART), pulmonary complications of HIV-1/AIDS continue to be a major cause of morbidity and mortality in HIV-1-infected patients, with bacterial pneumonia and chronic obstructive pulmonary disease (COPD) being the most commonly identified pulmonary diseases. Following pneumonia, these individuals experience a decrement in lung function, which is not observed in HIV-1-uninfected populations, and a subset of HIV-1-infected smokers develop an accelerated form of emphysema. However, the mechanisms underlying the increased risk of pneumonia and COPD in HIV-1-infected individuals are not well understood. In this regard, smoking and COPD are associated with a re-programming of alveolar macrophages towards an immune phenotype associated with immunoregulation. In HIV-1-infected subjects, increased expression of the anti-inflammatory cytokine IL-10 in blood and bronchoalveloar lavage (BAL) fluid occurs. Our preliminary data show that alveolar macrophages (AMs) from HIV-1-infected smokers and nonsmokers secrete increased amounts of IL-10 in response to lipopolysaccharide (LPS) compared to uninfected individuals and that cigarette smoke exposure reduced LPS-induced TNF-alpha secretion from AMs. Importantly, a link between increased expression of the coinhibitory receptor programmed death 1 (PD-1) on blood monocytes and IL-10 secretion in HIV-1-infected subjects has been observed. PD-1 is upregulated on T cells in the setting of chronic antigen exposure, contributing to T cell dysfunction and an inability to clear HIV-1. Our preliminary data further show that HIV-1- specific CD4+ and CD8+ T cells in the lung have upregulated expression of PD-1 compared to T cells in blood, resulting in a dysfunctional T cell phenotype. Based on these findings, we hypothesize that the immunoregulatory consequences of increased IL-10 secretion from AMs, a dysfunctional T cell phenotype and HIV-1-induced immunosuppression combine to predispose the HIV-1-infected lung to infection and injury, thereby hastening the development of COPD in HIV-1-infected smokers. Using blood and BAL cells from smokers and nonsmokers with and without HIV-1 infection, we will determine the effects of HIV-1 and smoking on PD-1 expression and IL-10 production by AMs in specific aim 1. The second aim will evaluate the relationship between PD-1 and IL-10 expression on AMs and their effects on T cell function in the lung before and after ART. In specific aim 3, we will use a case-control study to evaluate AM and T cell function in relation to physiologic measures of lung function and COPD development. These studies will advance our understanding of the effects of cigarette smoking on innate and adaptive immunity in the HIV- 1-infected lung and the relationship of these responses to the development of chronic lung disease.