Dysregulation of Alveolar Macrophage PPARγ, NADPH Oxidases, and TGFβ in Otherwise Healthy HIV-Infected Individuals.

Despite antiretroviral therapy (ART), respiratory infections increase mortality in individuals living with chronic human immunodeficiency virus (HIV) infection. In experimental and clinical studies of chronic HIV infection, alveolar macrophages (AMs) exhibit impaired phagocytosis and bacterial clearance. Peroxisome proliferator-activated receptor (PPAR)γ, NADPH oxidase (Nox) isoforms Nox1, Nox2, Nox4, and transforming growth factor-beta 1 (TGFβ) are critical mediators of AM oxidative stress and phagocytic dysfunction. Therefore, we hypothesized that HIV alters AM expression of these targets, resulting in chronic lung oxidative stress and subsequent immune dysfunction. A cross-sectional study of HIV-infected (n = 22) and HIV-uninfected (n = 6) subjects was conducted. Bronchoalveolar lavage (BAL) was performed, and AMs were isolated. Lung HO generation was determined by measuring HO in the BAL fluid. In AMs, PPARγ, Nox1, Nox2, Nox4, and TGFβ mRNA (quantitative real-time polymerase chain reaction) and protein (fluorescent immunomicroscopy) levels were assessed. Compared with HIV-uninfected (control) subjects, HIV-infected subjects were relatively older and the majority were African American; ∼86% were on ART, and their median CD4 count was 445, with a median viral load of 0 log copies/ml. HIV infection was associated with increased HO in the BAL, decreased AM mRNA and protein levels of PPARγ, and increased AM mRNA and protein levels of Nox1, Nox2, Nox4, and TGFβ. PPARγ attenuation and increases in Nox1, Nox2, Nox4, and TGFβ contribute to AM oxidative stress and immune dysfunction in the AMs of otherwise healthy HIV-infected subjects. These findings provide novel insights into the molecular mechanisms by which HIV increases susceptibility to pulmonary infections.