Alterations to the Bronchial Gene-Expression Effects of Tobacco Smoking in People Living With HIV

BACKGROUND: Although acquired immunodeficiency syndrome-related mortality has decreased since the introduction of antiretroviral therapy, the incidence of lung cancer in patients living with HIV (PLWH) remains high. Understanding the effects of tobacco smoke on airway gene expression in PLWH may provide insights into the elevated lung cancer risk associated with HIV. METHODS: Airway epithelial brushings were collected from 12 PLWH who smoke and 19 PLWH who have never smoked and profiled using RNA-seq. Linear models were used to identify genes differentially expressed between people who smoke and have never smoked and between people who previously smoked and have never smoked. Gene set enrichment analysis was used to validate smoking-related gene signatures across data sets. Data were integrated with gene expression data from a cohort of patients without HIV to identify genes differentially modulated by both smoking and HIV status. RESULTS: We found that previous smoking-related gene signatures are similarly associated with smoking in PLWH, including the persistent differential expression of a subset of "irreversibly altered" genes in people who previously smoked compared with people who have never smoked. We also identified and validated 2 gene signatures specifically modulated in people who smoke without HIV. CONCLUSIONS: Many of the effects of smoking on bronchial gene expression are shared between PLWH and non-HIV individuals. However, HIV-specific modulation of pathways linked to oxidative stress and epithelial integrity suggests potential mechanisms that may contribute to smoking-related outcomes that are more prevalent in PLWH, such as lung cancer.