Following the elite: Targeting immunometabolism to limit HIV pathogenesis

Abstract

Few people living with HIV (PLWH) have undetectable plasma viral acquisition and viral production in CD4 T cells in vitro. Furthermore, load, preserved CD4 T cell counts, low HIV reservoir and limited immune activation/inflammation in the absence of antiretroviral therapy (ART). These individuals are called elite controllers (ECs) and represent a heterogeneous minority amongst PLWH. However, overtime, some of them lose HIV control. ECs whomaintain viral control are called persistent controllers (PCs) while those who lose viral control are called transient controllers (TCs). As the underlying causes remain poorly understood, identifying factors associatedwith spontaneous loss of control will benefit HIV cure research [1,2]. Immunometabolism is rising to fame as the underlyingmechanisms betweenmetabolic reprogramming and immune response, thus providing a novel perspective of immunity in health and disease. In this issue of EBioMedicine, Tarancón-Diez et al. investigated the metabolic pathways linked with the spontaneous loss of control in HIV ECs [3]. Using metabolomics, investigators from the Spanish AIDS Research Network compared plasma metabolites and lipids in persistent and transient controllers. Before losing control, TCs showed an increase in aerobic glycolysis, dysregulated mitochondrial activity, oxidative stress and immunological activation. Plasma levels of valine were found to differentiate TCs from PCs. Valine and related catabolic intermediates that could enter the tricarboxylic acid (TCA) Krebs cycle were elevated due to a switch fromoxidative phosphorylation to glycolysis. In addition, lipid profiles characterized loss of viral control. Metabolites and lipid variations were associated with reduced HIV specific immune response demonstrated by a lower proportion of polyfunctional anti-HIV-Gag CD8 T-cells in TCs compared to PCs. An immune response requires a massive amount of energy to allow cell proliferation, maturation, and production of effector molecules. Upon activation, both CD4 and CD8 T cells switch from a “resting state” of oxidative phosphorylation to glycolysis, allowing for a faster albeit more “costly” means to produce energy. In the same line, ValleCasuso et al. found thatmetabolically active CD4 T cells are susceptible to HIV infection, regardless of their activation status [4]. Interestingly, targeting glycolysis and glutamine metabolism prevented HIV