Plasma GDF-15 Levels Are Associated With HIV Reservoir Markers Independently of Inflammation in People With HIV on Antiretroviral Therapy

BACKGROUND: People with human immunodeficiency virus (HIV) receiving antiretroviral therapy (ART) have increased risks of non-AIDS comorbidities. Growth differentiation factor 15 (GDF-15) is a mitokine released upon mitochondrial stress and is a validated aging biomarker. Herein, we assessed associations between plasma GDF-15 levels, inflammation, and HIV reservoir markers in ART-treated people with HIV (PWH). METHODS: Blood samples were collected from 78 ART-naive, 140 ART-treated PWH (median ART duration, 15.6 years) and 83 uninfected control participants. GDF-15 and markers of inflammation were quantified in plasma by enzyme-linked immunosorbent assay (ELISA) and multiplex assays. Integrated HIV DNA levels were measured in isolated CD4 T cells by ultrasensitive quantitative Alu polymerase chain reaction. Intracellular GDF-15 production was assessed ex vivo by flow cytometry, and in supernatants by ELISA after in vitro stimulations. RESULTS: Plasma GDF-15 levels were higher in ART-treated PWH compared to ART-naive PWH or controls, independently of age. Ex vivo, GDF-15 was produced by classical, intermediate, and nonclassical monocytes, but absent in T cells, B cells, natural killer cells, and dendritic cells. Plasma and monocyte intracellular GDF-15 levels correlated strongly (r = 0.96, P = .002). Plasma GDF-15 levels did not correlate with the majority of inflammatory markers quantified in plasma. Conversely, plasma GDF-15 levels correlated with the validated non-AIDS inflammatory comorbidity marker suPAR (soluble urokinase plasminogen activator receptor; r = 0.59, P < .001), as well as with integrated HIV DNA levels in CD4+ T cells (r = 0.47, P < .01). CONCLUSIONS: Plasma levels of GDF-15, mainly produced by monocytes, were positively associated with HIV reservoir markers and coincided with increased level of suPAR, suggesting that HIV persistence is associated with increased mitochondrial stress and comorbidity risks in ART-treated PWH.