Glucose Metabolism in T Cells and Monocytes: New Perspectives in HIV Pathogenesis

Abstract

Activation of the immune system occurs in response to the recognition of foreign antigens and receipt of optimal stimulatory signals by immune cells, a process that requires energy. Energy is also needed to support cellular growth, differentiation, proliferation, and effector functions of immune cells. In HIV-infected individuals, persistent viral replication, together with inflammatory stimuli contributes to chronic immune activation and oxidative stress. These conditions remain even in subjects with sustained virologic suppression on antiretroviral therapy. Here we highlight recent studies demonstrating the importance of metabolic pathways, particularly those involving glucose metabolism, in differentiation and maintenance of the activation states of T cells and monocytes. We also discuss how changes in the metabolic status of these cells may contribute to ongoing immune activation and inflammation in HIV- infected persons and how this may contribute to disease progression, establishment and persistence of the HIV reservoir, and the development of co-morbidities. We provide evidence that other viruses such as Epstein-Barr and Flu virus also disrupt the metabolic machinery of their host cells. Finally, we discuss how redox signaling mediated by oxidative stress may regulate metabolic responses in T cells and monocytes during HIV infection.

Keywords: CD4 T cells; CD8 T cells; Cardiovascular disease; Glucose transporter 1 (Glut1); HIV; HIV cure; HIV reservoir; Immune activation; Immunometabolism; Inflammation; Macrophage; Metabolism; Monocytes; Oxidative stress; SNAEs.

Fig. 1

Model illustrating metabolic exhaustion of CD4 + T cells in HIV-infected individuals. Activation of CD4 + T cells is maintained by increased cell surface Glut1 expression and glycolysis. We propose a model whereby CD4 + T cells have a low energy reserve and therefore, prolonged activation results in metabolic exhaustion and cell death. PPP, pentose phosphate pathway.

Fig. 2

Increased Glut1 cell surface expression and glycolysis maintain CD4 + T cell activation. Suppression of the abnormally high levels of glycolysis in CD4 + T cells may be an approach to reduce activation and therefore limit the number of potential HIV targets.

Fig. 3

Glucose metabolic profiles of M1 and M2 macrophages. (A) Glucose metabolic profile of M1 macrophages. Classically activated macrophages induce aerobic glycolysis that results in lactate production and increased synthesis and secretion of inflammatory cytokines. (B) Glucose metabolic profile of M2 macrophages. Alternatively activated macrophages trigger a metabolic profile predominated by oxidative phosphorylation (OxPhos).

Fig. 4

Monocyte metabolic profile changes during activation and differentiation. Monocytes display distinct metabolic profiles depending on their activation and differentiation states. Unactivated/naive monocytes are metabolically quiescent; their basal metabolic activity is low and ATP is derived primarily via oxidative phosphorylation (OxPhos). Upon activation/immune challenge monocytes shift to a state of metabolic activation characterized predominantly by Glucose transporter 1 expression (Glut1), increased glucose uptake, elevated glycolysis and biomass accumulation. Transition of monocytes to macrophage is characterized by further increases in Glut1 expression, glycolysis and biomass production. Activation of macrophages through ‘trained immunity’ may facilitate their transition to foam cells and instigate atherosclerosis.