Abstract
Background: To better understand why about 15% of people with human immunodeficiency virus-1 (PWH) on highly active antiretroviral therapy do not restore their CD4 count, we explored the link previously reported between glutamate plasma level and CD4 count.Methods: We recruited 44 adults with HIV-1 aviremic under antiretroviral therapy. Their peripheral blood concentrations in glutamate and γ-aminobutyric acid (GABA) were determined by ELISA. Flow cytometry was used to detect GABA receptor, reactive oxygen species (ROS) produced by monocytes, and programmed T-cell death. DNA-dependent protein kinase (DNA-PK) and p53 phosphorylation were analyzed by western blot. DNA damage was quantified by immunofluorescence.Results: We show that (1) some virologic responders present high plasma levels of glutamate and of its derivative, GABA; (2) monocytes express the GABA receptor GABA-B1; (3) GABA-B1 stimulation induces monocytic ROS production; (4) monocytes of PWH with high plasma levels of GABA release high amounts of ROS; and (5) monocyte-derived ROS oxidize the DNA of CD4+ T cells, creating double-strand breaks that activate DNA-PK and p53, and finally apoptosis. The intensity of this cascade of events is inversely correlated with the slope of CD4+ T-cell recovery in treated PWH. Conclusions: We propose that DNA damage resulting from ROS produced by GABA-activated monocytes plays a key role in impaired immune restoration. Consequently, GABA-B1 antagonists and/or ROS inhibitors might be a promising therapy for nonimmunologic responders. Furthermore, the same mechanism could be involved in CD4 loss in the natural course of the infection.Clinical Trials Registration NCT04028882.