Interferon-signaling pathways are upregulated in people with HIV with abnormal pulmonary diffusing capacity (DLCO)

Abstract

Objective: People with HIV (PWH) are at greater risk of developing lung diseases even when they are antiretroviral therapy (ART)-adherent and virally suppressed. The most common pulmonary function abnormality in PWH is that of impaired diffusing capacity of the lungs for carbon monoxide (DLCO), which is an independent risk factor for increased mortality in PWH. Earlier work has identified several plasma biomarkers of inflammation and immune activation to be associated with decreased DLCO. However, the underpinning molecular mechanisms of HIV-associated impaired DLCO are largely unknown. Design: Cross-sectional pilot study with PWH with normal DLCO (values greater than or equal to the lower limit of normal, DLCO ≥ LLN, N = 9) or abnormal DLCO (DLCO < LLN, N = 9). Methods: We compared the gene expression levels of over 900 inflammation and immune exhaustion genes in PBMCs from PWH with normal vs. abnormal DLCO using the NanoString technology. Results: We found that 26 genes were differentially expressed in the impaired DLCO group. These genes belong to 4 categories: 1. Nine genes in inflammation and immune activation pathways, 2. seven upregulated genes that are direct targets of the interferon signaling pathway, 3. seven B-cell specific genes that are downregulated, and 4. three miscellaneous genes. These results were corroborated using the bioinformatics tools DAVID (Database for Annotation, Visualization and Integrated Discovery) and GSEA (Gene Sets Enrichment Analysis). Conclusion: The data provides preliminary evidence for the involvement of sustained interferon signaling as a molecular mechanism for impaired DLCO in PWH.