Dysregulation of Alveolar Macrophage PPARγ, NADPH Oxidases, and TGFβ₁in Otherwise Healthy HIV-Infected Individuals

Abstract

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.

T cell-tropic HIV efficiently infects alveolar macrophages through contact with infected CD4+ T cells

“…Direct infection of macrophages can activate immune pathways including type I interferons that affect bystander function 76 , 77 and chemokines which recruit other immune cells 66 , 78 . A number of papers have explored mechanisms of macrophage functional impairment in people with HIV on ART that are not dependent on direct infection, which include gp120-induced inhibition of apoptosis 69 , nef-induced inhibition of phagocytosis 8 , 79 and downregulation of CD36 80 , as well as post-translational modification of Fc receptors 81 and changes in reactive oxygen species generation 82 . Notably, HIV proteins including gp120 and nef persist in bronchoalveolar lavage fluid in people with HIV on ART 69 , 83 .…”

History of tuberculosis is associated with lower exhaled nitric oxide levels in HIV-infected children

“…Alveolar macrophages play a central role in the defense against bacterial and mycobacterial infection; they may become infected with HIV and constitute the primary reservoir of the virus in the lung [37,38]. During HIV infection, alveolar macrophage function is compromised [37], with evidence of oxidative stress [39] and reduced ability to phagocytose and kill bacteria [40,41]. HIV-associated chronic activation of inflammatory cells in the alveolar space may further compromise the host response against infectious stimuli [42,43].…”

Los virus RNA inducen estrés oxidativo celular y los antioxidantes reducen la generación de partículas virales, tanto in vitro como in vivo

“…El tratamiento con un agonista de PPARγ aumenta los niveles de PPARγ, mejora el índice fagocítico de los macrófagos y disminuye el estrés oxidativo (106), respaldando el papel potencial de los agonistas de PPARγ para el tratamiento en las infecciones virales.…”