HIV-associated Chronic Obstructive Pulmonary Disease

HIV 相关的慢性阻塞性肺疾病

• 批准号: 8927053
• 负责人: Neerad Mishra
• 金额: $ 97.15万
• 依托单位: LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8927053
• 关键词: Acetylcholine; Acquired Immunodeficiency Syndrome; Address; Age; Alveolar; Animals; Anti-Retroviral Agents; Applications Grants; Architecture; Asthma; Biological Assay; Breathing; Bronchoalveolar Lavage Fluid; CCR5 gene; CXCR4 gene; Cause of Death; Cell Culture Techniques; Cell Line; Cells; Characteristics; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Chronic lung disease; Cigarette Smoker; Culture Media; Data; Development; Diffuse; Disease; Epidemiology; Epithelial; Epithelial Cells; Fibrosis; Forced expiratory volume function; Goblet Cells; Growth; Growth Factor Receptors; HIV; HIV Envelope Protein gp120; HIV Infections; HIV Seropositivity; HIV-1; Health; Hematoxylin and Eosin Staining Method; Highly Active Antiretroviral Therapy; Human; Hyperplasia; Incidence; Infection; Kinetics; Link; Longevity; Lung; Lung Compliance; Lung diseases; MUC5AC gene; Macaca; Macaca fascicularis; Metalloproteases; Metaplasia; Monkeys; Morbidity - disease rate; Mucociliary Clearance; Mucous body substance; Nicotinic Receptors; Obstructive Lung Diseases; Particulate; Pathway interactions; Patients; Population; Production; Pulmonary Emphysema; Reporting; Respiratory physiology; Risk Factors; Rodent Model; Role; SIV; Smoke; Smoker; Smoking; Smoking History; Staining method; Stains; Symptoms; Tenofovir; Testing; Trichrome stain; Virus Diseases; airway obstruction; antiretroviral therapy; base; chemokine; cigarette smoking; cytokine; early onset; gamma-Aminobutyric Acid; immunoreactivity; improved; morphometry; mortality; novel; pathogen; receptor; research study; respiratory; response; simian human immunodeficiency virus; synergism

 DESCRIPTION (provided by applicant): Prior to antiretroviral therapy (ART) including highly active ART (HAART), lung diseases were the major cause of death in AIDS patients. While ART has dramatically improved the morbidity and mortality in HIV-infected subjects, the incidence of chronic lung diseases such as chronic obstructive pulmonary disease (COPD), chronic bronchitis, and asthma remain high in this population. Smoking is highly prevalent in HIV-infected patients and smoking is the leading cause of COPD and chronic bronchitis in humans; however, with a similar smoking history COPD is more common and appears at younger age in HIV-infected than uninfected smokers. Recent reports suggest HIV as possible independent risk factors for the development of COPD. COPD is a progressive obstructive lung disease with no known cure. A common feature of COPD, asthma, and chronic bronchitis is overproduction of airway mucus. While airway mucus is important in the mucociliary clearance of inhaled pathogens and particulates, excessive mucus contributes to airway obstruction and is an excellent medium for the growth of many pathogens, which may accelerate the disease and cause COPD exacerbations. Our recent results indicate that, in spite of ART, SIV- and HIV-infected lungs contain substantial amounts of mucus and gp120 immunoreactivity. Moreover, cell culture studies indicated that primary cultures of normal human bronchial epithelial (NHBE) cells express CD4 and CXCR4 but not CCR5 and are productively infected by X4HIV-1. Moreover, as little as 10 ng/ml ≡ 8 x 10-11M X4-HIV gp120, induces mucus production and mucous cell hyperplasia/metaplasia in NHBE cells. Mucus production induced by HIV-1 gp120 is regulated by CXCR4, nicotinic acetylcholine receptors, and γ-aminobutyric acidA receptors. In rodent models, increasing evidence shows a synergy between cigarette smoke and some viral infections in the development of COPD. Based on these studies, we hypothesize that HIV-1 and cigarette smoke synergizes to accelerate the development of COPD, and HIV-gp120 promotes COPD exacerbation through excessive mucus production in the lung. Indeed, recent evidence links SHIV infection to airway obstructive changes in cynomolgus monkeys. In this grant application we propose to use cynomolgus macaques, SHIV infection, and HAART (combination of tenofovir, emtrictabine, and elvitegravir) to ascertain independent and/or synergistic roles of HIV, and cigarette smoke in the development of COPD (aim 1), and delineate the mechanism by which HIV-gp120 promotes mucus formation in NHBE cells (aim 2). We believe that this is the first study to understand the interaction between smoking, HIV infection, and ART in the development of COPD and will provide information that will help to reduce the incidence of COPD in HIV-infected subjects.

 描述(申请人提供)：在包括高效抗逆转录病毒疗法(HAART)在内的抗逆转录病毒疗法(ART)之前，肺部疾病是艾滋病患者的主要死亡原因。虽然抗逆转录病毒疗法显著改善了艾滋病毒感染者的发病率和死亡率，但慢性阻塞性肺疾病(COPD)、慢性支气管炎和哮喘等慢性肺部疾病在这一人群中的发病率仍然很高。吸烟在感染艾滋病毒的患者中非常普遍，吸烟是人类慢性阻塞性肺病和慢性支气管炎的主要原因；然而，有相似吸烟史的COPD更为常见，在感染艾滋病毒的吸烟者中出现的年龄比未感染的吸烟者年轻。最近的报告表明，艾滋病毒可能是慢性阻塞性肺疾病发展的独立危险因素。COPD是一种进行性阻塞性肺疾病，目前尚无治愈方法。慢性阻塞性肺疾病、哮喘和慢性支气管炎的一个共同特征是呼吸道粘液产生过多。虽然呼吸道粘液在清除吸入的病原体和微粒的粘液纤毛方面很重要，但过量的粘液会导致呼吸道阻塞，是许多病原体生长的绝佳媒介，这些病原体可能会加速疾病并导致COPD加重。我们最近的结果表明，尽管存在抗逆转录病毒治疗，SIV和HIV感染的肺含有大量的粘液和gp120免疫反应。此外，细胞培养研究表明，原代培养的正常人支气管上皮(NHBE)细胞表达CD4和CXCR4，但不表达CCR5，并能有效感染X4HIV-1。此外，10 ng/mlHIV8×10-11mX4-≡gp120可诱导NHBE细胞产生粘液和粘液细胞的增生/化生。HIV-1gp120诱导的粘液产生受CXCR4、烟碱型乙酰胆碱受体和γ-氨基丁酸A受体的调节。在啮齿动物模型中，越来越多的证据表明，在COPD的发展过程中，香烟烟雾和一些病毒感染之间存在协同作用。在这些研究的基础上，我们假设HIV-1和香烟烟雾协同作用加速COPD的发展，而HIV-gp120通过在肺内过度产生粘液促进COPD的恶化。事实上，最近的证据将食蟹猴的SIV感染与呼吸道阻塞的变化联系起来。在这项赠款申请中，我们建议使用食蟹猴、SHIV感染和HAART(替诺福韦、恩曲他滨和依维替格韦的组合)来确定HIV和香烟烟雾在COPD发展中的独立和/或协同作用(目标1)，并描述HIV-gp120促进NHBE细胞粘液形成的机制(目标2)。我们相信，这是第一个了解吸烟、HIV感染和ART在COPD发展过程中相互作用的研究，并将提供有助于降低HIV感染者COPD发病率的信息。