Immunometabolism is a key factor for the persistent spontaneous elite control of HIV-1 infection

Abstract

Background Approximately 25% of elite controllers (ECs) lose their virological control by mechanisms that are only partially known. Recently, immunovirological and proteomic factors have been associated to the loss of spontaneous control. Our aim was to perform a metabolomic approach to identify the underlying mechanistic pathways and potential biomarkers associated with this loss of control. Methods Plasma samples from EC who spontaneously lost virological control (Transient Controllers, TC, n = 8), at two and one year before the loss of control, were compared with a control group of EC who persistently maintained virological control during the same follow-up period (Persistent Controllers, PC, n = 8). The determination of metabolites and plasma lipids was performed by GC-qTOF and LC-qTOF using targeted and untargeted approaches. Metabolite levels were associated with the polyfunctionality of HIV-specific CD8 + T-cell response. Findings Our data suggest that, before the loss of control, TCs showed a specific circulating metabolomic profile characterized by aerobic glycolytic metabolism, deregulated mitochondrial function, oxidative stress and increased immunological activation. In addition, CD8 + T-cell polyfunctionality was strongly associated with metabolite levels. Finally, valine was the main differentiating factor between TCs and PCs. Interpretation All these metabolomic differences should be considered not only as potential biomarkers but also as therapeutic targets in HIV infection. Fund This work was supported by grants from Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Fondos FEDER; Red de Investigación en Sida, Gilead Fellowship program, Spanish Ministry of Education and Spanish Ministry of Economy and Competitiveness.

Non-Invasive Plasma Glycomic and Metabolic Biomarkers of Post-treatment Control of HIV

“…While no studies have evaluated the impact of plasma metabolic alterations in ATI, one study observed a glycolytic plasma pro le in transient HIV elite controllers (TECs) compared to persistent elite controllers (PECs). 51 Moreover, glutamic acid was shown to be elevated in PECs compared to TECs, 51 corresponding to our observation that glutamate metabolism associated with delayed time to HIV rebound. In totality, a global Warburg phenotype has now emerged as a classic manifestation of HIV infection.…”

Distinct lipid profile, low-level inflammation, and increased antioxidant defense signature in HIV-1 elite control status

“…Our finding is consistent with a recent study, where spontaneous loss of virologic control and transition from EC status was associated with increased oxidative stress and deregulated mitochondrial function prior to loss of control. Hence, oxidative stress could also be a potential determinant of EC status ( Tarancon-Diez et al., 2019 ). Oxidative stress might be beneficial for HIV-1 replication, and glutathione deficiency is associated with impaired survival in HIV-1 infection.…”

HIV-1 Infection and Glucose Metabolism Reprogramming of T Cells: Another Approach Toward Functional Cure and Reservoir Eradication

“…Another group found contradictory features of HICs compared with HAART treated subjects, that CD8+ T cells from HICs show lower levels of HIF-1A gene expression and higher of VHL, a counteracting gene of HIF-1 ( 86 ), implying that cells from HICs are less primed for glycolysis and activation. The link between metabolism profile and HIV-1 control is further verified by the longitudinal analysis of transient HICs which observed deregulation of metabolites mainly involved in glycolysis, TCA and amino acid metabolism associated with changed Gag-specific CD8+ T cells response preceding loss of viral control ( 87 ). After metabolic reprogramming through IL-15 treatment, CD8+ T cells from non-controllers displayed increased fatty acid uptake and mitochondrial respiratory capacity together with enhanced HIV-1-suppressing capacity ( 86 ).…”