TGF-β/Smad signaling pathway dysregulation and differential PBMC-derived miRNA expression are associated with systemic inflammation in people living with HIV: a cross-sectional study

Persistent systemic inflammation in people living with HIV (PLWH) is associated with non-AIDS comorbidities despite virologically suppressive antiretroviral therapy (ART). The transforming growth factor-β (TGF-β)/Smad signaling pathway is a central immunoregulatory axis; however, its potential coordination with peripheral blood mononuclear cell (PBMC)-derived microRNA (miRNA) expression and the mechanistic associations with monocyte activation and hepatic inflammation remain uncharacterized. In this exploratory cross-sectional study ( n = 70; 33 PLWH, 37 HIV-negative controls), serum TGF-β1, soluble CD14 (sCD14), C-reactive protein (CRP), and interferon-γ-inducible protein 10 (IP-10/CXCL10) were quantified by enzyme-linked immunosorbent assay (ELISA); Smad2/3/4/7 and TGFβ-R1/R2 mRNA by quantitative reverse transcription PCR (RT-qPCR); and eight PBMC-derived miRNAs by RT-qPCR. Age- and sex-adjusted multivariable linear regression and partial Spearman rank correlation analyses, stratified by HIV status, were performed. PLWH-only multivariable sensitivity models additionally adjusted for age, sex, CD4 + T-cell count, and ART duration. PLWH exhibited significantly elevated sCD14 [10.56 (10.11, 10.81) vs. 9.61 (9.31, 9.89) log2 ng/mL; p < 0.001; r_rb = + 0.78] and downregulated TGF-β1 [3.44 (2.14, 3.89) vs. 4.61 (4.04, 5.09) log2 ng/mL; p < 0.001; r_rb = − 0.62] and Smad4 mRNA ( p = 0.013; r_rb = − 0.35). Three PBMC-derived miRNAs were significantly upregulated in PLWH: miR-7-5p, miR-9-5p, and miR-519d-3p (all p ≤ 0.030). Stratified correlation analysis showed that the miRNA–TGF-β/Smad correlation structure was reorganized in PLWH relative to controls, with Smad2-anchored miRNA networks predominating in PLWH and Smad3-anchored networks in controls. Age- and sex-adjusted regression indicated that miR-519d-3p was inversely associated with TGF-β1 ( p = 0.044), and that lower Smad3 and TGFβ-R2 levels were linked to elevated CRP ( β = −0.54; p = 0.020 and β = −0.61; p = 0.027). Four PBMC-derived miRNAs (miR-519d-3p, miR-7-5p, miR-103a-3p, miR-9-5p) were positively associated with sCD14 ( β = 0.11–0.13; all p ≤ 0.019) in the full analytical sample. In PLWH-only multivariable sensitivity models, the TGFβ-R2–CRP association persisted ( β = −0.94; p = 0.015), whereas the sCD14–miRNA associations were attenuated. Coordinated PBMC-derived miRNA dysregulation was associated with two hypothesis-generating inflammatory patterns in the full analytical sample: TGF-β/Smad attenuation linked to CRP elevation, with PLWH-only multivariable support for the TGFβ-R2–CRP association, and PBMC-derived miRNA associations with monocyte activation (sCD14) that require further validation. These findings warrant validation in larger longitudinal cohorts with comprehensive clinical metadata and cell-type-resolved functional assays.