HIV-associated Chronic Obstructive Pulmonary Disease

HIV 相关的慢性阻塞性肺疾病

基本信息

批准号：
9100911
负责人：
Neerad Mishra
金额：
$ 61.43万
依托单位：
LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
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/9100911
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 Pulmonary Fibrosis Reporting Respiratory Signs and Symptoms Respiratory physiology Risk Factors Rodent Model Role SIV Smoke Smoker Smoking Smoking History Staining method Stains Tenofovir Testing Trichrome stain Viral Respiratory Tract Infection 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 response simian human immunodeficiency virus synergism

项目摘要

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.

说明（由申请人提供）：在包括高活性 ART (HAART) 在内的抗逆转录病毒治疗 (ART) 之前，肺部疾病是 AIDS 患者死亡的主要原因，虽然 ART 显着降低了 HIV 感染者的发病率和死亡率。慢性阻塞性肺病（COPD）、慢性支气管炎和哮喘等慢性肺部疾病的发病率在该人群中仍然很高。艾滋病毒感染者中吸烟非常普遍，而且吸烟是最主要的。人类慢性阻塞性肺病和慢性支气管炎的病因；然而，与未感染艾滋病毒的吸烟者相比，具有相似吸烟史的慢性阻塞性肺病更常见，并且出现的年龄更小。慢性阻塞性肺病、哮喘和慢性支气管炎的一个共同特征是气道粘液产生过多，而气道粘液对于清除吸入的粘膜纤毛非常重要。与病原体和颗粒物相比，过多的粘液会导致气道阻塞，并且是许多病原体生长的极好介质，这可能会加速疾病并导致 COPD 恶化。我们最近的研究结果表明，尽管有 ART，SIV 和 HIV 感染的肺部仍然存在。此外，细胞培养研究表明，正常人支气管上皮 (NHBE) 细胞的原代培养物表达 CD4 和 CXCR4，但不表达。 CCR5 和 X4HIV-1 均能有效感染，只需 10 ng/ml ≠ 8 x 10-11M X4-HIV gp120，即可诱导 HIV-1 诱导的 NHBE 细胞产生粘液和粘液细胞增生/化生。 gp120 受 CXCR4、烟碱乙酰胆碱受体和γ-氨基丁酸A受体。在啮齿动物模型中，越来越多的证据表明香烟烟雾和某些病毒感染在慢性阻塞性肺病的发展中具有协同作用。根据这些研究，我们发现HIV-1和香烟烟雾可以协同加速慢性阻塞性肺病的发展。事实上，最近的证据表明，SHIV 感染与食蟹猴的气道阻塞性变化有关。在本拨款申请中，我们建议使用食蟹猴、SHIV 感染和 HAART（替诺福韦、恩曲他滨和埃替拉韦的组合）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），以及描述 HIV-gp120 促进 NHBE 细胞中粘液形成的机制（目标 2）。这是第一项了解吸烟、艾滋病毒感染和抗逆转录病毒治疗在慢性阻塞性肺病发展中相互作用的研究，并将提供有助于降低艾滋病毒感染者慢性阻塞性肺病发病率的信息。