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Elevated Plasma GDF-15 Levels are Associated with the Immune Non-Responder Phenotype in People with HIV
Aida López López1,2, Jacobo Alonso Domínguez1, Inés Martínez Barros1
1Virology and Pathogenesis Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), Complexo Hospitalario Universitario de Vigo, SERGAS-UVigo, 36213, Vigo, Spain.
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 (β = 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.
