Gene expression differences in differentially methylated sites associated with HIV status and cocaine use

BackgroundEpigenome studies of human HIV-1 (HIV) in whole blood have uncovered a growing list of differentially methylated genes associated with either HIV acquisition, disease progression, or both. Cocaine use is associated with increased disease severity, and methylation changes in some of the HIV-associated genes mediate this effect. Many of these genes are critical players in innate immune response, including both regulators and targets of interferon-alpha and NF-kB activation. However, no study to date has evaluated the gene expression dynamics for these genes in the context of HIV. MethodsTargeted gene expression analyses were performed on 588 people who used illicit drugs within a harmonized cohort comprised of the Vancouver People Who Inject Drugs Study (VPWIDS) using RNAseq in whole blood, including 227 people living with HIV (PLWH). Eighteen genes were selected from six recent epigenome-wide association studies to test for differential expression by HIV status. Both gene-level and transcript-level expression changes were estimated using negative binomial regression models. ResultsNine of the 18 target genes exhibited significant upregulation in PLWH after multiple hypothesis testing correction: EPSTI1, IFI44L, IFIT3, MX1, NLRC5, PARP9, PLSCR1, RIN2, and RSAD2. Transcript-level analysis detected additional upregulation of isoforms for genes CD44, RASSF3, and TAP1. Stratified analysis by cocaine use revealed MX1 and RSAD2 to be exclusively upregulated among PLWH who recently used cocaine. Pathway analysis identified significant dysregulation in the interferon alpha/beta signaling pathway. ConclusionsWe confirm the dysregulation of genes previously reported to have differential methylation among PLWH. Results from this study support the model of epigenetic changes altering gene expression for key immune genes such as NLRC5 and MX1, and demonstrate systemic dysregulation of genes involved in innate immune function.