Subset Remodeling of MAIT and NK Cells Correlates With Immune Reconstitution in People Living With HIV Following Four Years of Antiretroviral Therapy

ABSTRACT Despite effective viral suppression, a subpopulation of people living with HIV (PLWH) receiving combination antiretroviral therapy (ART) experience a suboptimal immunological response, failing to restore CD4 + T‐cell counts to levels deemed indicative of good immune recovery. Innate immune cell dysregulation, particularly in mucosal‐associated invariant T (MAIT) and natural killer (NK) cells, is increasingly recognized as a key contributor to immune reconstitution. However, the dynamic changes, interactive crosstalk, and potential roles of these immune cells in immune reconstitution remain poorly understood. A total of 89 participants were enrolled, including 29 healthy controls and 60 HIV‐infected individuals, who were classified as immune responders (IRs, CD4 ≥ 500 cells/µL; n = 34) and suboptimal immunological responders (SIRs, CD4 < 500 cells/µL; n = 26) on the basis of immune recovery status. Longitudinal flow cytometric analysis was performed to assess the phenotypic changes in MAIT and NK cell subsets in peripheral blood mononuclear cells (PBMCs) before treatment (T0) and after 4 years of ART (T4). Correlation analysis was conducted to explore their associations with CD4 + T‐cell recovery. After 4 years of ART, both IRs and SIRs exhibited persistent depletion of total MAIT and invariant natural killer T (iNKT) cells, whereas pretreatment‐diminished CD56 bright and CD56 dim NK cell subsets increased significantly. MAIT cells also underwent phenotypic remodeling in both groups, with decreased CD4 − CD8 + and increased CD4 − CD8 − subsets. Notably, these cell subset proportions and quantitative changes correlated significantly with CD4 + T‐cell counts in IRs but not SIRs. In IRs, CD4 + T‐cell recovery positively correlated with baseline CD4 − CD8 − MAIT and CD56 bright NK cell numbers, but negatively with baseline CD4 − CD8 + MAIT cell numbers. Correlation networks revealed distinct MAIT–NK interactions across ART stages. LASSO models integrating MAIT and NK subsets achieved high predictive accuracy, highlighting the dynamic role of CD4 − CD8 + MAIT cells in immune reconstitution. Our study highlights the dynamic correlations between and within MAIT and NK cell subset proportions in PLWH, revealing that phenotypic remodeling rather than absolute cell counts plays a key role in immune reconstitution. CD4 − CD8 + MAIT cells show time‐dependent predictive shifts, reflecting functional adaptation. These findings identify MAIT and NK subset dynamics as potential biomarkers and therapeutic targets for enhancing immune recovery of PLWH during ART.