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.

Oxidative Stress during HIV Infection: Mechanisms and Consequences

“…Supporting this, activation of the latent infection was triggered by modest changes in the cell redox potential (25 mV) [144]. Such changes can be induced either directly by HIV proteins or indirectly through the induction of proinflammatory cytokines such as TNF- α [145]. …”

Doubly Labeled Water Method and Accelerometer for the Measurement of Energy Expenditure in Human Immunodeficiency Virus-Infected Patients

“…The authors also reported that the higher energy expenditure in the group with lipodystrophy possibly were affected by the differences in HIV disease severity, as that group exhibited significantly lower CD4 + cell counts. HIV-infected people present a chronic immune activation, even with viral suppression by ART use, which is associated with incomplete CD4 + T cell recovery, increased cellular metabolic activity, and other HIV complications that can influence energy metabolism [19]. …”

Emerging Role and Characterization of Immunometabolism: Relevance to HIV Pathogenesis, Serious Non-AIDS Events, and a Cure

“…HIV infection is associated with changes in T cell metabolism critical for viral replication but is also linked to T cell activation and depletion (3). The hyperactive (20, 21) and exhaustive (22, 23) phenotype associated with CD4 + T cells during HIV infection contributes to a gradual decline in CD4 T cell numbers and reduced functionality of surviving cells (25, 26).…”

“…Furthermore, HIV infection increases glycolytic flux in CD4 + T cells, and inhibition of glycolysis reduces viral production (7). The consequences of dysfunctional glucose metabolism in T cells and monocytes during HIV infection were reviewed comprehensively (3); however, metabolic dysfunction may impose unique responses in different subpopulations of immune cells. For example, the metabolic demands of effector CD4 + T cells and the shift from the high ATP–producing OxPhos to the less-efficient energy-producing aerobic glycolysis may encourage “CD4 T cell metabolic catastrophe” and cell death (3).…”

“…The metabolic shift usually occurs via increased expression of nutrient transporters [e.g., glucose transporters (1, 2)], increased generation of glycolytic enzymes, greater glycolytic flux, and increased rate of oxidative phosphorylation (OxPhos). The increased metabolic demands observed in activated T cells and monocytes are associated with immune activation and inflammatory responses, respectively (3). …”