Plasma GDF-15 levels are associated with HIV reservoir markers independently of inflammation in people with HIV on antiretroviral therapy

Background People with HIV (PWH) 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 a validated aging biomarker. Herein, we assessed associations between plasma GDF-15 levels, inflammation and HIV reservoir markers in ART-treated PWH. Methods Blood samples were collected from 78 ART-naïve, 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 ELISA and multiplex assays. Integrated HIV DNA levels were measured in isolated CD4 T-cells by ultrasensitive quantitative alu PCR. 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-naïve PWH or controls, independently of age. Ex-vivo, GDF-15 was produced by classical, intermediate, and non-classical monocytes, but absent in T-cells, B-cells, NK cells, and dendritic cells. Plasma and monocyte intracellular GDF-15 levels correlated strongly (r=0.96, p=0.002). 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<0.001), as well as with integrated HIV-DNA levels in CD4+ T cells (r=0.47, p<0.01). 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.