<p>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 (<i>n</i> = 7), individuals with low viral load (<i>n</i> = 14), and individuals with high viral load (<i>n</i> = 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.</p>