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    • We have also observed that elevated Glut

    2018-10-23

    We have also observed that elevated Glut1 on monocytes is associated with high sCD163 plasma levels within this HIV+ population, supporting a model by which chronic HIV infection drives metabolic activation of monocytes in response to inflammatory changes. This results from metabolic reprogramming within monocytes, switching metabolism from predominantly oxidative phosphorylation to glycolysis. This increase in glycolysis is supported by elevated cell surface Glut1 expression, facilitating more glucose entry into the cell to meet its energy requirements during cellular activation and promoting inflammation (Palmer et al., 2014a; Palmer et al., 2016). Indeed, increased expression of Glut1 on macrophages is a feature of herpes simplex virus type 1 that produce high levels of pro-inflammatory molecules, such as TNF and IL-6 (Freemerman et al., 2014). It is unknown whether the expression of CD14 and CD163 and the subsequent cleavage of their soluble products (sCD14 and sCD163) are independent of mechanisms that support metabolic reprogramming of monocytes. We have previously demonstrated that Glut1 expression is up-regulated in monocytes from HIV-infected compared to uninfected individuals, even after a mean of 9.3years of antiretroviral therapy (Palmer et al., 2014a). Further, expression of Glut1 is elevated on the intermediate subset of monocytes from HIV-infected women with subclinical cardiovascular disease, supporting a possible role for monocyte glucose metabolic reprogramming in the pathogenesis of non-AIDS comorbidities (Butterfield et al., 2017). Our study found an association between frailty and increased Glut1 expression on the total monocyte population, which marks activation of glycolysis. We did not observe an association between frailty and mitochondrial membrane potential as measured by DiOC6(3) fluorescence in monocytes. DiOC6(3) is a dye that stains mitochondria in live cells, and is used to measure mitochondrial trans‑membrane potential and mitochondrial integrity, which decrease with mitochondrial dysfunction preceding apoptosis (Macho et al., 1995). The effects of some HIV treatment regimens on mitochondrial dysfunction in adipose tissues are well established (Mccomsey et al., 2013). In a recent study comparing blood samples from HIV+ patients with samples from HIV negative controls, Yu and colleagues demonstrated that HIV infection was associated with an increase in mitochondrial membrane potential in CD4+ and CD8+ T cells (Yu et al., 2017). Lymphocytes from HIV+ individuals have also been shown to have significant defects in mitochondrial membrane potential compared to HIV negative controls, with monocytes largely unaffected (Perrin et al., 2012). Our findings do not rule out a role for mitochondrial dysfunction in the pathogenesis of frailty. It is plausible that HIV and/or particular antiretroviral therapy regimens may impact parameters of mitochondrial functions, such as mass, structure and efficiency in terms of ATP production, that have not been evaluated here. It has previously been shown that HIV infection and aging are associated with T cell activation (Cobos Jiménez et al., 2016; Yao et al., 2011). However, we observed no differences in activation measured by CD38 and HLA-DR overexpression between frail and non-frail HIV-infected men. Our findings are consistent with other studies where markers of T cell activation did not predict the development of serious non-AIDS events (Tenorio et al., 2014). Likewise, we observed no association between frailty and metabolic activation marked by Glut1 levels on T cells. Dyslipidemia is well documented in virologically suppressed HIV positive patients on antiretroviral therapy (Schulte-Hermann et al., 2016). In fact, HIV infection is associated with significantly deranged plasma lipid profiles compared to HIV negative controls (Wong et al., 2014). Wong and colleagues have identified key lipid classes, in particular, the GM3 ganglioside and monohexosylceramide subclasses, which were negatively associated with HIV infection (Wong et al., 2014), however their clinical relevance in the context of age-related co-morbidities in HIV infection is not well established. In our study, these lipid classes were negatively associated with frailty, and the GM3 ganglioside subclass was positively correlated with quality of life. Our study also found that the lipid classes, triacylglycerol and phosphatidylethanolamine, that have been shown to predict cardiovascular disease in HIV+ people (Wong et al., 2014), were in our study significantly associated with frailty and poorer quality of life. Despite this, there are only very limited data demonstrating a relationship between precise lipid species and age-related non-AIDS morbidity.