Although substantial progress has been made in the treatment of HIV infection, the regulatory mechanisms linking genetic variation, transcriptomic alterations, immune-cell changes, and post-transcriptional control remain poorly defined. A systematic multi-omics framework is needed to identify key molecular drivers and candidate biomarkers associated with HIV infection. We performed an integrated multi-omics analysis combining protein quantitative trait locus (cis-pQTL)-based summary-data Mendelian randomization (SMR) for 555 plasma proteins with multiple HIV-related genome-wide association study (GWAS) outcomes, followed by HEIDI testing to exclude linkage. In parallel, we conducted differential expression analyses of mRNA and miRNA from blood of healthy controls (n = 7), individuals with low viral load (n = 14), and individuals with high viral load (n = 16). Weighted gene co-expression network analysis (WGCNA) was used to define co-expression modules, which were overlaid with SMR hits and differentially expressed genes (DEGs) and further embedded into transcription-factor (TF) regulon networks. Plasma WFDC2 levels were quantified by ELISA in untreated HIV-infected, ART-treated, and control cohorts. Immune-cell deconvolution, gene set enrichment, and miRNA-mRNA network modeling were used to characterize the functional context of candidate genes.Lastly, HIV-associated cellular models were constructed, followed by functional validation experiments based on WFDC2 overexpression. Transcriptomic profiling revealed strong concordance between the HVL-CON and LVL-CON contrasts, identifying 803 commonly up-regulated and 1,108 commonly down-regulated genes. Integration of SMR results with DEGs highlighted eight overlapping candidate genes-including WFDC2-whose encoded proteins were supported by both genetic instruments and transcriptional deregulation. These genes were embedded in immune-related co-expression modules and TF regulons. Among them, WFDC2 emerged as a key candidate, showing consistent down-regulation at the mRNA and protein levels, extensive correlations with inferred immune-cell subsets, and co-expressed genes enriched for chromatin remodeling, antiviral defense, RNA processing, and translation. Plasma WFDC2 concentrations were reduced in untreated HIV-infected individuals and partially restored under ART compared with healthy controls. Differentially expressed miRNAs potentially targeting WFDC2 and its co-expressed partners suggested additional post-transcriptional regulation. This multi-omics framework delineates a layered network connecting genetic regulation, transcriptional changes, immune-cell shifts, and miRNA-mediated control in HIV infection. Within this network, WFDC2 stands out as a putative hub integrating immune modulation and RNA metabolic pathways, and may represent a promising biomarker and potential therapeutic targets in HIV.
Yan et al. (Mon,) studied this question.