Single-cell profiling reveals IFI44L as a central regulator of immune dysregulation in high HIV viral load

Human Immunodeficiency Virus (HIV) infection impairs the immune system, diminishing its ability to defend against pathogens and increasing susceptibility to infections and diseases. To gain a comprehensive understanding of the heterogeneity, functions, and regulatory mechanisms of immune cells affected by different HIV viral loads, we investigated the biological impacts of HIV infection on the human body. We reanalyzed a publicly available peripheral blood mononuclear cell (PBMC) single-cell RNA sequencing dataset (GSE157829) comprising three people living with HIV with high viral load (HL-HIV), three people living with HIV with low viral load (LL-HIV), and one healthy control donor. We constructed single-cell immune atlases that represent different viral load profiles. We also analyzed the dynamic changes in specific immune cell subpopulations to gain insights into their signaling pathways, developmental trajectories, and key transcriptional regulators. At the single-cell level, non-classical monocyte subpopulations, specifically ncMono_LYN_TCF7L2 and ncMono_IL32, functioned as immunosurveillance elements but also activated pro-inflammatory pathways, leading to immune activation. B_CD83 subpopulation was critical in B cell development, facilitating B cell differentiation and tolerance. Naive.T_TNFAIP3 subpopulation exhibited anti-inflammatory effects and protected against aberrant apoptosis. Central memory T (TCM)_TCF7_CCR7 subpopulation played a crucial role in regulating the expansion of HIV-specific CD8⁺ T cells and maintaining the immune response. Additionally, we observed a significant enrichment of IFI44L-positive subpopulations across different cell types, particularly in HL-HIV samples. Our findings demonstrate that HIV infection increases the complexity of immune cell subpopulations. Notably, IFI44L has emerged as a potential disease hub gene in HL-HIV samples, highlighting its potential as a novel biomarker for HIV.