Abstract
Infection of primary CD4+ T cells with HIV-1 coincides with an increase in glycolysis. We investigated the expression of glucose transporters (GLUT) and glycolytic enzymes in human CD4+ T cells in response to infection with HIV-1. We demonstrate the co-expression of GLUT1, GLUT3, GLUT4, and GLUT6 in human CD4+ T cells after activation, and their concerted overexpression in HIV-1 infected cells. The investigation of glycolytic enzymes demonstrated activation-dependent expression of hexokinases HK1 and HK2 in human CD4+ T cells, and a highly significant increase in cellular hexokinase enzyme activity in response to infection with HIV-1. HIV-1 infected CD4+ T cells showed a marked increase in expression of HK1, as well as the functionally related voltage-dependent anion channel (VDAC) protein, but not HK2. The elevation of GLUT, HK1, and VDAC expression in HIV-1 infected cells mirrored replication kinetics and was dependent on virus replication, as evidenced by the use of reverse transcription inhibitors. Finally, we demonstrated that the upregulation of HK1 in HIV-1 infected CD4+ T cells is independent of the viral accessory proteins Vpu, Vif, Nef, and Vpr. Though these data are consistent with HIV-1 dependency on CD4+ T cell glucose metabolism, a cellular response mechanism to infection cannot be ruled out.
Highlights
The CD4+ T cell compartment is an essential component of the adaptive immune system that regulates the initiation or suppression of humoral, as well as cellular immune responses, and the establishment of immunological memory
For the first time, investigated the full range of glucose transporters that are expressed in human CD4+ T cells on activation and infection with human immunodeficiency virus type 1 (HIV-1), being GLUT1, 3, 4, and 6
We demonstrated that HIV-1 infected CD4+ T cells have increased glucose uptake and concerted overexpression of this full set of glucose transporters compared with uninfected cells
Summary
The CD4+ T cell compartment is an essential component of the adaptive immune system that regulates the initiation or suppression of humoral, as well as cellular immune responses, and the establishment of immunological memory. The transition from quiescent to activated effector CD4+ T cells requires increased biosynthesis and energy to support cell growth, proliferation, and expression of effector molecules, which is achieved through a metabolic switch upon. TCR stimulation and co-stimulation of CD28 leads to signaling through AKT (Protein Kinase B), PI3K (Phosphatidylinositol 3-Kinase), mTOR (mammalian Target of Rapamycin), and ERK (Extracellular signal Regulated Kinase), that results in increased expression and targeting of nutrient transporters to the cell membrane [9,10,11,12]. A Myc-driven transcriptional program ensures that metabolic enzymes and nutrient transporters are coordinately expressed upon CD4+ T cell activation [13]. Glucose metabolism is important to support the biosynthesis of effector cytokines, as in the absence of flux through the glycolytic pathway, the enzyme GAPDH acts as a translational repressor of mRNAs, including interferon gamma (IFNγ) and IL-2 [14]
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