γ-Aminobutyric Acid-Induced Monocytic Reactive Oxygen Species Impair CD4 Restoration in Treated Adults With HIV-1

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.