Widespread activation of immunity and pro-inflammatory programs in peripheral blood leukocytes of HIV-infected patients with impaired lung gas exchange.
HIV infection is associated with impaired lung gas transfer as indicated by a low diffusing capacity (DLCO), but the mechanisms are not well understood. We hypothesized that HIV-associated gas exchange impairment is indicative of system-wide perturbations that could be reflected by alterations in peripheral blood leukocyte (PBL) gene expression. Forty HIV-infected (HIV(+)) and uninfected (HIV(-)) men with preserved versus low DLCO were enrolled. All subjects were current smokers and those with acute illness, lung diseases other than COPD or asthma were excluded. Total RNA was extracted from PBLs and hybridized to whole-genome microarrays. Gene set enrichment analysis (GSEA) was performed between HIV(+) versus HIV(-) subjects with preserved DLCO and those with low DLCO to identify differentially activated pathways. Using pathway-based analyses, we found that in subjects with preserved DLCO, HIV infection is associated with activation of processes involved in immunity, cell cycle, and apoptosis. Applying a similar analysis to subjects with low DLCO, we identified a much broader repertoire of pro-inflammatory and immune-related pathways in HIV(+) patients relative to HIV(-) subjects, with up-regulation of multiple interleukin pathways, interferon signaling, and toll-like receptor signaling. We confirmed elevated circulating levels of IL-6 in HIV(+) patients with low DLCO relative to the other groups. Our findings reveal that PBLs of subjects with HIV infection and low DLCO are distinguished by widespread enrichment of immuno-inflammatory programs. Activation of these pathways may alter the biology of circulating leukocytes and play a role in the pathogenesis of HIV-associated gas exchange impairment.
Division of Pulmonary & Critical Care Medicine, Harborview Medical Center, University of Washington, Seattle, Washington KCrothers@medicine.washington.edu.
Kristina
K
Crothers
Division of Pulmonary & Critical Care Medicine, National Jewish Health, Denver, Colorado.
Irina
I
Petrache
Pulmonary Section, Department of Veterans Affairs Medical Center, Decatur, Georgia Division of Pulmonary, Allergy, Critical Care, & Sleep Medicine, Emory University, Atlanta, Georgia.
Cherry
C
Wongtrakool
Division of Pulmonary & Critical Care Medicine, Yale University, New Haven, Connecticut.
Patty J
PJ
Lee
Division of Pulmonary & Critical Care Medicine, Medical University of South Carolina, Charleston, South Carolina.
Lynn M
LM
Schnapp
Division of Pulmonary & Critical Care Medicine, Harborview Medical Center, University of Washington, Seattle, Washington.
Sina A
SA
Gharib
D000328:Adult; D015658:HIV Infections / Q000150:complications* / Q000276:immunology*; D006801:Humans; D007962:Leukocytes / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011656:Pulmonary Emphysema / Q000209:etiology*; D011659:Pulmonary Gas Exchange; D012129:Respiratory Function Tests; D059467:Transcriptome
Human immunodeficiency virus; lung diffusing capacity; microarray; network