Background
Through the degradation of cytosolic structures and proteins, autophagy generates macromolecules for energy production which allows efficient anti-HIV T-cell responses. Extracellular Acyl-CoA-Binding Protein (ACBP) inhibits autophagy, tricarboxyclic acid (TCA) cycle and oxidative phosphorylation in mouse models, mainly through binding to the GABAA receptor. Herein, we assessed the levels of circulating ACBP and its influence on T-cell function in people living with HIV (PLWH) on antiretroviral therapy (ART) and tested whether inhibition of ACBP-receptor binding could be used in preclinical models to improve the immune function in PLWH on ART.
Methods
Plasma ACBP and cytokines were quantified by ELISA in 50 PLWH on effective ART (mean duration of 14.7 years) and 30 controls with similar age. In vitro, recombinant ACBP (recACBP) was added at increasing concentrations up to 10µg/mL on PBMCs from PLWH on ART and controls, T-cell responses and autophagy levels were assessed by flow cytometry. A synthetic GABAAreceptorg2 chain peptide was used to prevent binding of ACBP to this receptor, as described by Dr Kroemer’s group.
Results
ACBP levels were higher in PLWH on ART compared to controls (median 127.5 vs 78.1 ng/mL, p=0.03), independently of age and sex.
In ART-treated PLWH, plasma ACBP levels correlated with levels of pro-inflammatory Th1 and Th2 cytokines, angiogenesis and innate inflammation. Conversely, ACBP levels were inversely associated with plasma IL21 levels (r=-0.54, p<0.01).
ACBP levels were associated with secretion of energy production intermediary macromolecules glutamate and α-ketoglutarate.
Addition of recACBP to PBMCs before stimulation with anti CD3 or HIV peptides prevented CD4 and CD8 T-cell cytokine secretion as well as cell proliferation. Also, recACBP addition decreased expression of autophagy markers Beclin1, p62 and ULK1 in both CD4 and CD8 T-cells stimulated with anti-CD3. Addition of GABAArg2 peptides had no influence on ACBP inhibiting T-cell cytokine production and proliferation upon anti-CD3 or HIV peptide stimulation.
Conclusions
Higher plasma ACBP levels in PLWH on ART were associated with inflammation, and markers of T-cell dysfunction. Extracellular ACBP directly inhibited autophagy and T-cell function. Our results indicate that another receptor than the GABAA receptor might be involved, compelling the assessment of ACBP inhibitory mechanism to develop new inhibitors aimed at improving anti-HIV T-cell responses in PLWH, towards an HIV cure.
Table or Figure
