More than 30 million people worldwide are living with HIV. In individuals with chronic HIV infection, lung disease is a major cause of morbidity and mortality. HIV infection increases the incidence of chronic obstructive pulmonary disease (COPD), as well as other lung diseases. In fact, the incidence of respiratory symptoms and/or abnormal pulmonary function tests (PFTs) in people with HIV is as high as 60% in some studies. The mechanisms causing non-infectious pulmonary disease in HIV are poorly understood. It has been suggested that immune dysregulation from HIV is an important contributor to the process. In addition, direct effects of the virus on lung cells, oxidative stres, chronic low-grade infection of the lung, and antiretroviral therapy (ART) use may contribute to the pathogenesis of these disorders. An increased understanding of the molecular mechanisms involved in HIV-associated lung disease may help identify novel biomarkers, facilitate preventative approaches, and guide the development of novel therapies. However, studies to determine the exact pathogenesis of COPD in chronic HIV infection have been limited. To better define the molecular mechanisms of COPD in chronic HIV, we propose to extensively phenotype HIV infected subjects using cutting-edge imaging technologies, bronchoscopy, and advanced immune assays, and correlate these measures to the incidence and progression of COPD. We hypothesize that in patients with chronic HIV infection, repeated injury to the small airways and the pulmonary vasculature result in emphysematous changes and pulmonary vascular remodeling leading to COPD. Using a cohort of patients with chronic HIV infection, we will identify subjects with airway obstruction and compare them to subjects with normal lung function. We will further phenotype subjects using high resolution computed tomography (HRCT), echocardiography, and positron emission tomography (PET) with 13N2-saline. These imaging techniques will provide quantitative anatomic and physiologic data, including extremely sensitive measurements of lung and pulmonary vascular destruction, regional lung ventilation, and regional lung perfusion. These data will be correlated with assessment of T cell activity and oxidative stress in bronchoalveolar lavage (BAL) fluid and peripheral blood. In addition, we will broadly explore other potential causes for COPD in this population with metabolomic, and gene expression studies. We will also explore the potential role of ART in COPD pathogenesis by utilizing a unique cohort of elite HIV controllers.
The specific aims are: 1) To determine the relationship between chronic activation of T cells, lung injury and COPD in chronic HIV;2) To determine levels of oxidative stress in the lung of patients with chronic HIV and define the contribution to lung injury and COPD.
In individuals with chronic HIV infection, lung disease is a major cause of morbidity and mortality. HIV infection increases the incidence of chronic obstructive pulmonary disease (COPD), but the mechanisms for this association are unknown. An increased understanding of the molecular mechanisms involved in HIV- associated lung disease may help identify novel biomarkers, facilitate preventative approaches, and guide the development of novel therapies.
|Kleinsteuber, Katja; Corleis, Björn; Rashidi, Narges et al. (2016) Standardization and quality control for high-dimensional mass cytometry studies of human samples. Cytometry A 89:903-913|
|Cho, Josalyn L; Medoff, Benjamin D (2015) Lung T cells in HIV infection. Driven to exhaustion? Am J Respir Crit Care Med 191:370-1|