Increased glucose metabolic activity is associated with CD4+ T-cell activation and depletion during chronic HIV infection

Abstract

Objectives Glucose metabolism plays a fundamental role in supporting the growth, proliferation and effector functions of T cells. We investigated the impact of HIV infection on key processes that regulate glucose uptake and metabolism in primary CD4+ and CD8+ T cells. Design and methods Thirty-eight HIV-infected treatment-naive, 35 HIV+/combination antiretroviral therapy, seven HIV+ long-term nonprogressors and 25 HIV control individuals were studied. Basal markers of glycolysis [e.g. glucose transporter-1 (Glut1) expression, glucose uptake, intracellular glucose-6-phosphate, and L-lactate] were measured in T cells. The cellular markers of immune activation, CD38 and HLA-DR, were measured by flow cytometry. Results The surface expression of the Glut1 is up-regulated in CD4+ T cells in HIV-infected patients compared with uninfected controls. The percentage of circulating CD4+Glut1+ T cells was significantly increased in HIV-infected patients and was not restored to normal levels following combination antiretroviral therapy. Basal markers of glycolysis were significantly higher in CD4+Glut1+ T cells compared to CD4+Glut1− T cells. The proportion of CD4+Glut1+ T cells correlated positively with the expression of the cellular activation marker, HLA-DR, on total CD4+ T cells, but inversely with the absolute CD4+ T-cell count irrespective of HIV treatment status. Conclusion Our data suggest that Glut1 is a potentially novel and functional marker of CD4+ T-cell activation during HIV infection. In addition, Glut1 expression on CD4+ T cells may be exploited as a prognostic marker for CD4+ T-cell loss during HIV disease progression.

Glucose Transporter 1–Expressing Proinflammatory Monocytes Are Elevated in Combination Antiretroviral Therapy–Treated and Untreated HIV+ Subjects

“…This observation agrees with previously reported findings that markers of innate immune activation can remain elevated after the initiation of cART (26,(36)(37)(38). Although HIV infection caused upregulation of cell-surface Glut1 expression on monocytes in this study and on CD4 + T cells in our previous study (23) In addition to cardiovascular disease, proinflammatory monocytes are expanded in cancer (49), kidney disease (50), and liver disease (51). An increased risk for each of these age-related diseases is associated with HIV infection.…”

“…Intracellular Glut1 (Glut1 c-term ) was detected as previously described (23), except that the permeabilizing component A of the Intra Stain kit (Dako) was diluted 1:1 with 13 PBS before use, and the secondary Ab was DyLight conjugated.…”

HIV-1 transgenic rats display mitochondrial abnormalities consistent with abnormal energy generation and distribution

“…Interestingly, much of the proteomic data has been corroborated by previous publications for on the ETC [10–12] and glycolyic pathway [55–57] albeit in alternative cell types or animal models. Together these data suggest the HIV-1 viral proteins produce chronically dysfunctional mitochondria, and these mitochondrial alterations can contribute to the HAND functional pathology.…”

“…Previous work on glycolysis levels in cells exposed to HIV-1 viral proteins have produced varied results. In a variety of cells, exposure to certain HIV-1 viral proteins in vitro or HIV-1 virus in vivo results in increased glycolysis [55–57]. Conversely, isolates of blood from HIV-1 infected individual have also demonstrated decreased glycolysis [58].…”

Current topics in HIV-1 pathogenesis: The emergence of deregulated immuno-metabolism in HIV-infected subjects

“…For instance, T-cell activation requires the up-regulation of glycolysis (catabolism of glucose) to meet the biosynthetic and bioenergic needs of cell proliferation, survival, and immune function including the synthesis of cytokines [2,5,84]. As mentioned earlier, since HIV-1 infection is characterized by long-lasting and excessive inflammation/cell activation, most of infected patients display up-regulation in glucose metabolic activity [6,[85][86][87][88]. These observations are consistent with higher glucose uptake/trafficking in HIV-1-infected patients and elevated metabolite pool sizes such as sedoheptulose 7-phosphate and ribose-phosphate [86].…”