HIV-1 Gp120 clade B/C induces a GRP78 driven cytoprotective mechanism in astrocytoma

Abstract

HIV-1 clades are known to be one of the key factors implicated in modulating HIV-associated neurocognitive disorders. HIV-1 B and C clades account for the majority of HIV-1 infections, clade B being the most neuropathogenic. The mechanisms behind HIV-mediated neuropathogenesis remain the subject of active research. We hypothesized that HIV-1 gp120 clade B and C proteins may exert differential proliferation, cell survival and NeuroAIDS effects in human astrocytoma cells via the Unfolded Protein Response, an endoplasmic reticulum- based cytoprotective mechanism. The differential effect of gp120 clade B and C was evaluated using for the first time a Tandem Mass Tag isobaric labeling quantitative proteomic approach. Flow cytometry analyses were performed for cell cycle and cell death identification. Among the proteins differentiated by HIV-1 gp120 proteins figure cytoskeleton, oxidative stress, UPR markers and numerous glycolytic metabolism enzymes. Our results demonstrate that HIV-1 gp120 B induced migration, proliferative and protective responses granted by the expression of GRP78, while HIV-1 gp120 C induced the expression of key inflammatory and pro-apoptotic markers. These novel findings put forward the first evidence that GRP78 is a key player in HIV-1 clade B and C neuropathogenic discrepancies and can be used as a novel target for immunotherapies.

HIV-1 Envelope Protein gp120 Promotes Proliferation and the Activation of Glycolysis in Glioma Cell

“…After treating cells with gp120 at 100 ng/mL for 10 continuous days we observed an increase in the number of viable cells in all cell lines investigated, including the 965 primary glioma cell line ( Figure 1 A). The gp120 concentration we used has been reported in the literature as effective for inducing signaling in glioma cells and it is also consistent with the gp120 serum concentration in HIV patients [ 32 , 33 ]. A significant difference in cell growth between gp120-treated and untreated cells was not observed at earlier time points (less than 5 days of treatment) ( Supplemental Figure S1A ).…”

“…Our results revealed a reduction in the amino acid levels in cells treated with gp120. Together with the reduction in urea ( Table 1 ) and the upregulation of molecules involved in protein synthesis, previously identified by our group [ 32 ], such as the RPS2, RPS13, RPS15 ribosomal proteins and number of initiation and elongation factors as eIF4A1, eIF4G1, PABPC1 and eEFG1, these findings indicate the predominance of anabolic processes over catabolic processes and active protein synthesis. It has been shown that glutamine uptake is essential for growth in a number of cancers [ 84 , 85 , 86 , 87 , 88 , 89 ].…”

“…As we recently published, quantitative Tandem Mass Tag (TMT) isobaric labeling quantitative proteomics analysis revealed that gp120 causes upregulation of a number of proteins involved in glycolysis and in the tricarboxylic acid (TCA) cycle in glioma cells including enolase 2 (ENO2), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and malate dehydrogenase [ 32 ].…”

Endoplasmic Reticulum Chaperones in Viral Infection: Therapeutic Perspectives

“…In the case of human immunodeficiency virus 1 (HIV-1), Lopez et al ( 81 ) reported differences in cell survival or apoptosis of U87-MG astrocytoma cells depending on whether the cells were infected by the B or C strains. The authors concluded that this could explain differences in neuropathogenesis induced by the two clades ( 82 ).…”

Diversity in heat shock protein families: functional implications in virus infection with a comprehensive insight of their role in the HIV-1 life cycle

“…HSPA5 was noted to interact with the envelope protein during its folding in the endoplasmic reticulum (Earl et al 1991 ), and other isoforms were implicated to interact with viral proteins like Tat, Gag and Vpr. HIV-1 Clade B gp120 induces HSPA5 and other ER stress markers, as compared to HIV-1 Clade C gp120 in astrocytoma cells (López et al 2017 ). HIV-1 tat is also known to induce HSPA5 and other ER stress markers (Ma et al 2016 ).…”