Abstract
MicroRNAs (miRNAs) play a crucial role in gene regulation, including HIV, where they influence viral replication and immune response. This study aims to identify key miRNAs involved in HIV pathogenesis, using bioinformatics and cohort validation to explore their potential as biomarkers for early detection, disease monitoring, and therapeutic targets. HIV-host interactomes for HIV-1 and HIV-2 were analyzed using STRING and Cytoscape to construct interaction networks for key HIV receptors. Gene-disease associations, GWAS data, and tissue expression profiles were retrieved to refine miRNA predictions, utilizing multiMiR and enrichment analyses to identify significant regulatory interactions. Blood samples of HIV-positive untreated patients were collected longitudinally over six months (baseline, 1, 3, and 6 months) after antiretroviral therapy initiation to validate bioinformatics predictions using Fluidigm qRT-PCR. We identified key miRNAs involved in HIV regulation by ranking HIV-disease interactors, highlighting miR-590-3p as the most significant, along with other miRNAs associated with critical pathways. Enrichment analysis of miRNA targets revealed their involvement in immune signaling, apoptosis regulation, and disease-related pathways, particularly in rheumatoid arthritis and neoplastic processes. Significant reductions were observed as early as 1 month for miR-590-3p, miR-1-3p, miR-146a-5p, let-7b-5p, miR-155-5p and miR-16-5p (p < 0.0001 for all) compared with ART-naive patients, indicating an early therapeutic response. Our study identifies key miRNAs as significant HIV-disease interactors through in silico prediction and cohort validation. Our findings lay the groundwork for future studies exploring the functional roles of these miRNAs and their potential as biomarkers of immune recovery or targets for therapeutic modulation in ART-treated populations.