Abstract
BackgroundTobacco smoking induces immunomodulatory and pro-inflammatory effects associated with transcriptome changes in monocytes and other immune cell types. While smoking is prevalent in HIV-infected (HIV+) individuals, few studies have investigated its effects on gene expression in this population. Here, we report whole-transcriptome analyses of 125 peripheral blood monocyte samples from ART-treated HIV+ and uninfected (HIV−) men enrolled in the Multicenter AIDS Cohort Study (MACS) (n = 25 HIV+ smokers, n = 60 HIV+ non-smokers, n = 40 HIV− non-smoking controls). Gene expression profiling was performed using Illumina HumanHT-12 Expression BeadChip microarrays. Differential expression analysis was performed with weighted linear regression models using the R limma package, followed by functional enrichment and Ingenuity Pathway analyses.ResultsA total of 286 genes were differentially expressed in monocytes from HIV+ smokers compared with HIV− non-smokers; upregulated genes (n = 180) were enriched for immune and interferon response, chemical/stress response, mitochondria, and extracellular vesicle gene ontology (GO) terms. Expression of genes related to immune/interferon responses (AIM2, FCGR1A-B, IFI16, SP100), stress/chemical responses (APAF1, HSPD1, KLF4), and mitochondrial function (CISD1, MTHFD2, SQOR) was upregulated in HIV+ non-smokers and further increased in HIV+ smokers. Gene expression changes associated with smoking in previous studies of human monocytes were also observed (SASH1, STAB1, PID1, MMP25). Depressive symptoms (CES-D scores ≥ 16) were more prevalent in HIV+ tobacco smokers compared with HIV+ and HIV− non-smokers (50% vs. 26% and 13%, respectively; p = 0.007), and upregulation of immune/interferon response genes, including IFI35, IFNAR1, OAS1-2, STAT1, and SP100, was associated with depressive symptoms in logistic regression models adjusted for HIV status and smoking (p < 0.05). Network models linked the Stat1-mediated interferon pathway to transcriptional regulator Klf4 and smoking-associated toll-like receptor scaffolding protein Sash1, suggesting inter-relationships between smoking-associated genes, control of monocyte differentiation, and interferon-mediated inflammatory responses.ConclusionsThis study characterizes immune, interferon, stress response, and mitochondrial-associated gene expression changes in monocytes from HIV+ tobacco smokers, and identifies augmented interferon and stress responses associated with depressive symptoms. These findings help to explain complex interrelationships between pro-inflammatory effects of HIV and smoking, and their combined impact on comorbidities prevalent in HIV+ individuals.
Highlights
Tobacco smoking induces immunomodulatory and pro-inflammatory effects associated with transcriptome changes in monocytes and other immune cell types
Depressive symptoms (CES-D score ≥ 16) were more prevalent among HIV+ TS+ and TS− compared with HIV− TS− participants (50% and 27%, vs. 13%, respectively; p = 0.007), while there was no differences in prevalence of alcohol use, cocaine use, body mass index (BMI), and HCV serostatus
Increased expression of canonical immune/interferon response induced genes, including IFI35, IFNAR1, OAS1, OAS2, PGM2, PSMD1, SP100, and STAT1 was associated with depressive symptoms in logistic regression models adjusted for HIV status and smoking
Summary
Tobacco smoking induces immunomodulatory and pro-inflammatory effects associated with transcriptome changes in monocytes and other immune cell types. While smoking is prevalent in HIV-infected (HIV+) individuals, few studies have investigated its effects on gene expression in this population. HIV+ individuals have higher rates of comorbidities associated with smoking compared with persons in the general population, including lung cancer [5], infectious and chronic obstructive pulmonary diseases (COPD) [6, 7], and cardiovascular disease [8,9,10]. Smoke from tobacco combustion contains over 1000 chemicals including carcinogens, toxins, particulates, and reactive oxidative species (ROS) [11, 12]. Cellular responses to these insults are mediated in part through immune cell activation and modulation of inflammation, oxidative stress, and DNA damage responses [11,12,13]. While smokingassociated signaling pathways and their effects on cellular transcriptional programs have been previously described in immune cells [11], the molecular mechanisms underlying responses to tobacco smoking, especially in HIV+ tobacco smokers, remain poorly understood
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