br The Role of Glucose Metabolism in HIV Pathogenesis br

The Role of Glucose Metabolism in HIV Pathogenesis
Metabolic Regulation of Monocytes Monocytes dramatically change their metabolic phenotype from oxidative to glycolytic metabolism when activated in humans (Dietl et al., 2010; Cramer et al., 2003), similar to what is observed in T cells. In a study conducted by Vats and colleagues, classical activation of murine macrophages by IFNγ and lipopolysaccharide (LPS) strongly induced glucose uptake with a concomitant suppression of fatty voltage gated potassium channel uptake and oxidation (Vats et al., 2006). Evidence suggests that classically activated pro-inflammatory M1 macrophages demonstrate enhanced glycolytic metabolism and reduced mitochondrial activity. A similar metabolic profile represents the metabolic basis of “trained immunity” or “innate immune memory”, in which trained monocytes have increased aerobic glycolysis regulated through an Akt–mTOR–HIF-1α pathway (Cheng et al., 2014). In contrast, anti-inflammatory M2 macrophages are characterized by high mitochondrial oxidative phosphorylation, have enhanced spare respiratory capacity (Van den Bossche et al., 2015), and are reliant upon β-oxidation of fatty acids (Johnson et al., 2012; Mills and O\'Neill, 2016). However, Hollenbaugh and colleagues more recently showed that while oxidative metabolism was increased, glucose uptake and glycolysis were reduced when the monocytic cell line U1 was infected with HIV (Hollenbaugh et al., 2011). This discrepancy is likely due to differences in activating stimuli and may relate to the use of cell lines as sources of monocytes, further complicated by the use of distinct monocytic cell lines U1 and U937 in their experiments. It is possible that, similar to CD4+ T cells, both metabolic programs are upregulated in monocytes and macrophages during activation, but glycolysis predominates. From a bioenergetics perspective, engaging oxidative phosphorylation maximizes ATP production so why would activated monocytes engage a less efficient energy generating pathway? It may be argued that engagement of glycolysis creates substrates for DNA and cell membrane synthesis to facilitate growth and differentiation of monocytes. Another possibility for the glycolytic shift by M1 macrophages is to facilitate optimal response suited for the rapid, short-term bursts of activation needed at sites of infection or inflammation as discrete metabolic patterns will result in varying levels of metabolites that can directly impact cellular function (O\'Neill and Pearce, 2016). Citrate accumulation in the M1 macrophage is essential for the production of proinflammatory mediators such as NO, ROS, and prostaglandins (Infantino et al., 2011). In addition, metabolites and intermediates may serve as important signaling or regulatory molecules in immune cells. For example, the glycolytic enzyme GAPDH can bind to the AU-rich elements within the 3′ UTR of IFN-γ mRNA in T cells, and may disengage glycolysis and control effector cytokine production. Thus, aerobic glycolysis may also serve as a signaling mechanism to control inflammatory responses in immune cells (Chang et al., 2013).
Physiological Regulation of Glucose Metabolism: Oxidative Stress
Conclusion Increased glucose metabolism in CD4+ T cells and monocytes is a hallmark of HIV infection and is driven by HIV proteins and inflammatory responses. This heightened metabolic state is regulated by Glut1 and required to maintain activation of CD4+ T cells, making them preferential targets for HIV infection and replication. Immune activation and reduced CD4+ T cell counts in HIV infected individuals are associated with increased expression of the glucose transporter Glut1 on CD4+ T cells. Increased glycolytic metabolism of monocytes is proposed as an underlying mechanism in the development of SNAEs such as frailty, cardiovascular complications and diabetes. We have highlighted the role of oxidative stress in HIV disease pathogenesis, noting that diminished levels of glutathione, a key mitochondrial antioxidant, is observed in HIV+ individuals. Understanding the associations between metabolic dysfunction and oxidative stress in immune cells may provide an opportunity to involve antioxidant therapies in the care and management of HIV-associated co-morbidities (Nguyen et al., 2014).