Serum IL-27 and IL-35 Levels as Complementary Biomarkers of Immune Status in HIV-Positive Individuals

BACKGROUND/AIMS: Human immunodeficiency virus (HIV) infection remains a worldwide public health challenge, primarily due to its disruption of immune regulation and cytokine homeostasis. As members of the interleukin (IL)-12 family, IL-27 and IL-35 contribute to immune regulation, although they may have functionally opposing roles. The objective of this study was to explore the association between IL-27 and IL-35 levels, viral load, and immune parameters in individuals living with HIV compared with healthy subjects. MATERIALS AND METHODS: A total of 45 HIV-positive individuals and 45 healthy controls, matched for age and sex, were enrolled in this cross-sectional study. Serum IL-27 and IL-35 concentrations were measured using enzyme-linked immunosorbent assay. Correlations between cytokine levels, HIV-ribonucleic acid (RNA), and T-cell subsets were assessed using Spearman’s rho. Logistic regression and receiver operating characteristic (ROC) analyses were conducted to identify predictors of HIV-positivity and to assess diagnostic performance, while multivariate patterns were examined using partial least squares discriminant analysis (PLS-DA). RESULTS: IL-27 levels were significantly lower and IL-35 levels were significantly higher in HIV-positive patients than in controls (p<0.01 for both). IL-27 was negatively correlated with HIV RNA (r=-0.40, p=0.02) and the neutrophil-to-lymphocyte ratio (r=-0.33, p=0.03), and positively correlated with total T-cell percentage (r=0.34, p=0.04). Conversely, IL-35 showed a strong positive correlation with HIV-RNA (r=0.66, p<0.001) and strong negative correlations with CD4 count (r=-0.47, p=0.001) and CD4 percentage (r=-0.78, p=0.001). In logistic regression, IL-35 was an independent positive predictor of HIV positivity [odds ratio (OR) =2.08, 95% confidence interval (CI) =1.29-3.34, p=0.003], whereas IL-27 was inversely associated with HIV positivity (OR =0.993, 95% CI =0.988-0.998, p=0.004). ROC analysis demonstrated high discriminative ability for IL-35 [area under the curve (AUC) =0.863] and moderate discriminative ability for IL-27 (AUC =0.717); their combination achieved the highest accuracy (AUC =0.898; sensitivity =80%; specificity =91%). PLS-DA confirmed that elevated IL-35 levels, decreased IL-27 levels, and CD4 depletion were the major contributors to HIV-related immunosuppression. CONCLUSION: IL-27 and IL-35 exhibit opposing immunomodulatory patterns in HIV infection. Decreased IL-27 and elevated IL-35 levels reflect disease activity and immune dysregulation. While IL-35 serves as an independent biomarker of immunosuppression, combined assessment of IL-27 and IL-35 increases diagnostic accuracy in distinguishing HIV-positive individuals from healthy controls.