Dual T-cell exhaustion and hyperactivation profiles identify patients with advanced HIV at high risk for fungal...

To characterize immune alterations in PLWH across disease stages and identify laboratory indicators for diagnosing fungal co-infections.

We conducted a comprehensive cross-sectional study comparing laboratory immunological parameters-including lymphocyte subsets, activation/exhaustion markers, and plasma cytokines-across patient groups stratified by co-infection type and CD4⁺ T cell count. Statistical significance was assessed using false discovery rate correction.

The most severe immunological compromise was observed in patients with advanced HIV disease (CD4⁺ ≤199 cells/µL) and co-infections, who exhibited profound pan-lymphopenia and a dissociated T cell profile featuring both hyperactivation (HLA-DR/CD38) and exhaustion (loss of CD28). Compared to patients with other opportunistic infections, those with fungal co-infections displayed a distinct immune phenotype characterized by significantly lower CD4⁺ T cell counts (51.32 ± 47.41 vs. 134.27 ± 130.12 cells/µL, q = 0.004) and B cell counts (65.74 ± 56.13 vs. 108.30 ± 101.10 cells/µL, q = 0.024), alongside elevated CD8⁺ T cell activation. Patients with localized Talaromyces marneffei infection had significantly higher CD4⁺ T, CD8⁺ T, and natural killer cell counts than those with disseminated disease, underscoring the importance of preserved cellular immunity in pathogen containment. No significant differences were observed across fungal pathogens or sites of cryptococcal disease. Correlation analysis revealed a strong positive association between HIV viral load and interleukin-10(R² = 0.587, r = 0.632, 95% CI: 0.473 to 0.755, P = 0.014).

Specific immunological parameters-particularly severe CD4⁺ and B cell lymphopenia with concurrent CD8⁺ T cell hyperactivation-provide an objective basis for identifying PLWH at high risk for fungal infections. These findings highlight the potential value of adjunctive immunomodulatory strategies alongside antiviral therapy in this patient population.

Not applicable.