Elevated Plasma GDF-15 Levels are Associated with the Immune Non-Responder Phenotype in People with HIV

Abstract

INTRODUCTION: Most people with HIV (PWH) achieve immune recovery with antiretroviral therapy (ART); however, a clinically relevant subset, known as immune non-responders (INRs), fails to restore CD4+ T-cell counts despite sustained virological suppression and shows persistent immune dysfunction. Growth differentiation factor 15 (GDF-15), a stress-responsive cytokine associated with inflammation, aging, chronic disease, and multimorbidity, has not been characterized across distinct HIV viro-immunological phenotypes. METHODS: We conducted an exploratory cross-sectional study including 80 PWH classified as ART-naïve individuals, virally suppressed INRs, elite controllers (ECs), and ART-treated immune responders (IRs), as well as 20 HIV-negative controls. Plasma GDF-15 levels were measured by immunoassay. Associations with log-transformed GDF-15 concentrations were assessed using multivariable linear regression including age, CD4+ T-cell nadir, and INR status. RESULTS: INRs showed the highest plasma GDF-15 levels (median, 1143.9 pg/ml), significantly exceeding those observed in ART-naïve individuals, ECs, IRs, and HIV-negative controls (all p ? 0.002). GDF-15 levels correlated positively with age, time since HIV diagnosis, and ART duration, and inversely with CD4+ T-cell nadir and the CD4/CD8 ratio (all p ? 0.001). In adjusted analysis, INR status remained independently associated with higher log-transformed GDF-15 levels (? = 0.271, 95% CI 0.062-0.480; p = 0.012), corresponding to 31.1% higher GDF-15 concentrations relative to non-INR participants. CONCLUSION: Plasma GDF-15 levels were higher in virally suppressed INRs than in other viro-immunological groups and remained independently associated with INR status after adjustment for selected covariates. These findings support further investigation of GDF-15 as a potential biomarker of incomplete immune recovery and residual biological stress in virally suppressed PWH. Prospective studies are warranted to validate its clinical and pathophysiological relevance.