CD4/CD8 ratio is associated with structural reorganization of vaccine-induced immune responses in people living with HIV

Background: Despite effective antiretroviral therapy and sustained viral suppression, people living with HIV (PLWH) continue to exhibit persistent immune activation and low-grade inflammation. Although the CD4/CD8 ratio is routinely monitored as a marker of immune health, the mechanisms underlying residual immune dysregulation remain incompletely understood. Methods: Peripheral blood mononuclear cells from PLWH and HC were collected before and one month after two doses of mRNA vaccination and analyzed by single-cell RNA sequencing with paired TCR profiling. Differential gene expression (DGE) and protein–protein interaction (PPI) network analyses were performed, and node degree distributions were compared among groups. TCR and bulk BCR repertoires were analyzed, and neutralizing antibody responses were assessed. PLWH were stratified by CD4/CD8 ratio. Results: Stratification by CD4/CD8 ratio revealed distinct immune states in PLWH. Differential genes from the normal CD4/CD8 ratios showed focused transcriptional activation with coordinated chemokine-associated communication, whereas those with low CD4/CD8 ratios exhibited broad transcriptional dysregulation and structural reorganization of gene-expression networks. This network signature was characterized by altered PPI topology and significantly increased monocyte-specific node degree, independent of overall transcriptional complexity. Repertoire analyses demonstrated clonal skewing and reduced clonotype diversity in the low CD4/CD8 ratio group, consistent with impaired immune coordination. Conclusion: Vaccine-induced immune responses in PLWH are shaped by network-level organization associated with CD4/CD8 ratio–defined immune states. Low CD4/CD8 ratio group showed increased monocyte-specific PPI connectivity and clonal imbalance, suggesting altered vaccine-induced response dynamics not captured by conventional clinical markers.