Hiv- And Subclinical Cardiovascular Disease-Specific Transcriptomes In Nonclassical Monocytes: The Women'S Interagency Hiv Study

Objectives: Nonclassical monocytes (NCM) have patrolling functions relevant to atherosclerosis. While NCM have low surface CXCR4 expression in people with concurrent HIV and CVD (Mueller Cardiovasc Res 2019), the extent of CVD-related gene expression and the pathways involved are unknown. We described the gene transcription signature of NCM to provide insight into potential mechanisms of HIV-associated CVD. Methods: We identified transcriptomic changes in circulating NCM among women with and without chronic HIV infection. CVD was defined by plaques found on B-mode carotid artery ultrasound. The study included 23 HIV - CVD - , 21 HIV + CVD - , 20 HIV - CVD + , and 21 HIV + CVD + women, with these four groups matched by age (median = 45), race (95% minority) and smoking (86% ever-smokers). Using cryopreserved cells, we flow-sorted NCM (CD14 dim CD16+) and deep-sequenced their mRNA (average depth >40 million reads) to identify differentially expressed genes (DEG) contrasting HIV alone, CVD alone, and concurrent HIV + CVD + groups, versus HIV - CVD - , based on FDR-adjusted P<0.05. Results: After filtering to genes with raw counts >10 in >60% of participants, 11,343 protein coding genes were analyzed. HIV alone was associated with 10 DEGs on NCM (Figure). Women affected by both HIV and CVD had 93 DEGs, only six of which were shared by the HIV alone DEG signal. CVD alone was associated only with upregulated CDK18, which was also identified as a DEG in the HIV + CVD + group. Conclusion: Concurrent HIV and CVD (HIV + CVD + ) is associated with altered gene expression in NCMs relative to HIV - CVD - , generating responses that involve interleukins (IL32, IL4R), immune checkpoint inhibition (LAG3), chemokines (CCL4, CCL5) and lipid homeostasis (ABCD2).