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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\u2212) men enrolled in the Multicenter AIDS Cohort Study (MACS) (<jats:italic>n =<\/jats:italic>25 HIV+ smokers,<jats:italic>n<\/jats:italic>= 60 HIV+ non-smokers,<jats:italic>n<\/jats:italic>= 40 HIV\u2212 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<jats:italic>limma<\/jats:italic>package, followed by functional enrichment and Ingenuity Pathway analyses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 286 genes were differentially expressed in monocytes from HIV+ smokers compared with HIV\u2212 non-smokers; upregulated genes (<jats:italic>n<\/jats:italic>= 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 (<jats:italic>AIM2<\/jats:italic>,<jats:italic>FCGR1A-B<\/jats:italic>,<jats:italic>IFI16<\/jats:italic>,<jats:italic>SP100<\/jats:italic>), stress\/chemical responses (<jats:italic>APAF1<\/jats:italic>,<jats:italic>HSPD1<\/jats:italic>,<jats:italic>KLF4<\/jats:italic>), and mitochondrial function (<jats:italic>CISD1<\/jats:italic>,<jats:italic>MTHFD2<\/jats:italic>,<jats:italic>SQOR<\/jats:italic>) 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 (<jats:italic>SASH1<\/jats:italic>,<jats:italic>STAB1<\/jats:italic>,<jats:italic>PID1<\/jats:italic>,<jats:italic>MMP25<\/jats:italic>). Depressive symptoms (CES-D scores \u2265 16) were more prevalent in HIV+ tobacco smokers compared with HIV+ and HIV\u2212 non-smokers (50% vs. 26% and 13%, respectively;<jats:italic>p<\/jats:italic>= 0.007), and upregulation of immune\/interferon response genes, including<jats:italic>IFI35<\/jats:italic>,<jats:italic>IFNAR1<\/jats:italic>,<jats:italic>OAS1-2<\/jats:italic>,<jats:italic>STAT1<\/jats:italic>, and<jats:italic>SP100<\/jats:italic>, was associated with depressive symptoms in logistic regression models adjusted for HIV status and smoking (<jats:italic>p<\/jats:italic>&lt; 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This 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.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s40246-019-0247-x","type":"journal-article","created":{"date-parts":[[2019,11,28]],"date-time":"2019-11-28T18:03:12Z","timestamp":1574964192000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Transcriptomic analysis of monocytes from HIV-positive men on antiretroviral therapy reveals effects of tobacco smoking on interferon and stress response systems associated with depressive symptoms"],"prefix":"10.1186","volume":"13","author":[{"given":"David R.","family":"Lorenz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikas","family":"Misra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4964-5083","authenticated-orcid":false,"given":"Dana","family":"Gabuzda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,11,28]]},"reference":[{"issue":"10082","key":"247_CR1","doi-asserted-by":"publisher","first-page":"1885","DOI":"10.1016\/S0140-6736(17)30819-X","volume":"389","author":"GBDT Collaborators","year":"2017","unstructured":"Collaborators GBDT. 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