HIV-infected persons appear to be at higher risk for chronic obstructive pulmonary disease (COPD), although the clinical manifestations and underlying mechanisms of HIV-associated COPD remain unclear. The ongoing Study of HIV Infection in the Etiology of Lung Disease (SHIELD) cohort has recruited >2,000 participants to prospectively evaluate how HIV infection may enhance susceptibility to COPD. SHIELD data suggest that poorly controlled plasma HIV viremia accelerates lung function decline. Further, HIV-associated COPD is characterized by CD4+ T cell depletion occurring to a greater extent in the lung mucosa than in the periphery. Based on these findings, our central hypothesis is that the development and clinical manifestations of HIV- associated COPD are driven, at least in part, by HIV viral replication, CD4+ T cell depletion and CD8+ T cell immune activation in the lung mucosa.
In Aim 1, we identify and differentiate clinical, physiologic, and radiographic COPD phenotypes in HIV-infected compared to uninfected persons. Then, we prospectively follow these participants to define the clinical and patient-reported consequences of COPD phenotypes.
In Aim 2, we determine whether the presence and severity of HIV-associated COPD is correlated with depletion of lung CD4+ T cells.
In Aim 3, we test the hypothesis that lung CD4+ depletion and dysregulation is due to HIV infection and replication.
In Aim 4, we examine whether there is increased lung CD8+ T cell immune activation in HIV-associated COPD, due at least in part, to loss of CD4+ T cell regulatory mechanisms. Our multidisciplinary team of investigators provides clinical and research expertise in HIV, pulmonary diseases, and immunology, and have an established track record of productive collaboration in HIV and COPD. SHIELD provides an ideal study population and research infrastructure to perform these clinical and mechanistic studies. In summary, this proposal directly addresses critical gaps in our understanding of the clinical spectrum and consequences of HIV-associated COPD and will identify key biologic mechanisms contributing to the disease. Findings will inform the clinical management and development of interventions targeting HIV- associated COPD, and may also inform broader strategies for COPD in non-HIV infected populations.
Persons with HIV infection are at higher risk for chronic obstructive pulmonary disease (COPD), although the clinical manifestations and underlying mechanisms remain unclear. By studying a large, existing cohort of patients, the proposal will characterize the clinical spectrum and consequences of COPD in persons with HIV. Through a series of experiments in paired lung and blood samples, key immune mechanisms will be evaluated as contributors to COPD in HIV. Findings will inform the management of HIV-associated COPD, and perhaps also for COPD in persons without HIV.
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|Hansen, Erik C; Ransom, Monica; Hesselberth, Jay R et al. (2016) Diverse fates of uracilated HIV-1 DNA during infection of myeloid lineage cells. Elife 5:|
|Popescu, Iulia; Drummond, M Bradley; Gama, Lucio et al. (2016) HIV Suppression Restores the Lung Mucosal CD4+ T-Cell Viral Immune Response and Resolves CD8+ T-Cell Alveolitis in Patients at Risk for HIV-Associated Chronic Obstructive Pulmonary Disease. J Infect Dis 214:1520-1530|
|Leader, Joseph K; Crothers, Kristina; Huang, Laurence et al. (2016) Risk Factors Associated With Quantitative Evidence of Lung Emphysema and Fibrosis in an HIV-Infected Cohort. J Acquir Immune Defic Syndr 71:420-7|
|Brune, Kieran A; Ferreira, Fernanda; Mandke, Pooja et al. (2016) HIV Impairs Lung Epithelial Integrity and Enters the Epithelium to Promote Chronic Lung Inflammation. PLoS One 11:e0149679|
|Lambert, Allison A; Kirk, Gregory D; Astemborski, Jacquie et al. (2015) HIV Infection Is Associated With Increased Risk for Acute Exacerbation of COPD. J Acquir Immune Defic Syndr 69:68-74|
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