Patients infected with human immunodeficiency virus (HIV) are more prone to developing cancers, including glioblastomas (GBMs). The median survival for HIV positive GBM patients is significantly shorter than for those who are uninfected, despite the fact that they receive the same treatments. The nature of the GBM–HIV association remains poorly understood. In this study, we analyzed the effect of the HIV envelope glycoprotein gp120 on GBM cell proliferation. Specifically, we performed cell cycle, western blot, protein synthesis and metabolomics analysis as well as ATP production and oxygen consumption assays to evaluate proliferation and metabolic pathways in primary human glioma cell line, U87, A172 cells and in the HIVgp120tg/GL261 mouse model. Glioma cells treated with gp120 (100 ng/mL for 7–10 days) showed higher proliferation rates and upregulation in the expression of enolase 2, hexokinase and glyceraldehyde-3-phosphate dehydrogenase when compared to untreated cells. Furthermore, we detected an increase in the activity of pyruvate kinase and a higher glycolytic index in gp120 treated cells. Gp120 treated GBM cells also showed heightened lipid and protein synthesis. Overall, we demonstrate that in glioma cells, the HIV envelope glycoprotein promotes proliferation and activation of glycolysis resulting in increased protein and lipid synthesis.

Patients infected with human immunodeficiency virus (HIV-1) are more prone to developing cancers, including glioblastomas (GBMs). The median survival for GBM patients with HIV is significantly shorter than for HIV-negative GBM patients, despite the fact that they receive the same treatments. This difference indicates that HIV infection is associated with more aggressive tumor behavior and with treatment resistance. Earlier we demonstrated that gp120, a main glycoprotein in the HIV shell, stimulates glycolysis and protein synthesis in glioma cells. The purpose of this study was to evaluate the underlying gp120 dependent signaling mechanism in glioma cell. Using MAPK kinase antibody array and western blot assays we have identified the activation of MAP kinase and Akt/mTOR pathways in U87, A172, and primary glioma cells treated with gp120 (100 ng/ml) for 5 consequent days. Specifically, up regulation of pMEK1/2(Ser217/221), pERK(Thr202/Tyr224), pP90RSK(Thr359), pmTOR(S2448), pAkt(pS473), and pGSK3b(pS9) have been identified. These data coincide with previously obtained results showing that glioma cells treated with gp120 exhibit higher protein synthesis and proliferation rates compared to un-treated glioma cells. The use of pharmacological inhibitors of PI3K/Akt and ERK signaling reversed the stimulatory effect of gp120 on global protein synthesis, as revealed by flow cytometry analysis. Overall, we demonstrated that gp120 triggers activation of ERK and Akt signaling in glioma cells, resulting in increased protein synthesis and cell growth. This research was made possible by NIH grant number 1SC1GM122691 and Puerto Rico Science, Technology, and Research Trust grant 2016-00157.