Dysregulated inflammatory cytokines in MSM living with HIV who exhibited suboptimal immune reconstitution despite antiretroviral therapy (ART).

[INTRODUCTION] The relationship between serum cytokine levels and immunologic non-response in people living with HIV (PLWH) receiving antiretroviral therapy (ART) remains inadequately characterized. This study aimed to comprehensively characterize the serum cytokine profiles of men who have sex with men (MSM) living with HIV who exhibited different immunologic responses to ART.

[METHODS] We recruited MSM living with HIV and HIV-uninfected MSM (healthy controls, HC) in Guangzhou between June 1 to October 31, 2021. MSM living with HIV were classified as poor immunological responders (PIR, CD4+ T cell count <350 cells/μL) and good immunological responders (GIR, ≥ 350 cells/μL) after more than 24 months of ART. Blood samples were collected, and serum cytokines were quantified using Olink multiplex proximity extension assay (PEA).

[RESULTS] A total of 134 MSM were enrolled, including 44 HC, 52 GIR, and 38 PIR. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed significant difference in the PI3K-AKT signaling pathways between GIR and PIR. Six candidate cytokine markers (PD-L1, FGF-19, CD244, CD8α, 4E-BP1, and CASP-8) were identified by least absolute shrinkage and selection operator (LASSO) regression for the construction of diagnostic models. The corresponding area under the curve (AUC) based on these six candidate markers was 0.844 (95 %CI: 0.647-1.000) in the support vector machine (SVM) model. Notably, PD-L1 and FGF-19 were identified as the top2 important cytokines for distinguishing between GIR and PIR based on LASSO regression, random forest (RF), and SVM analyses. Furthermore, PD-L1 and FGF-19 levels were negatively correlated with CD4+ T cell count (r = -0.34) and CD4+/CD8+ T cell ratio (r = -0.29), respectively.

[CONCLUSIONS] Distinct serum cytokine profiles were observed among PLWH with divergent immunologic responses, offering novel insights into the pathogenesis of immunologic non-response and identifying serum cytokines as promising therapeutic targets.