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

// Sheila N. Lopez 1 , Madeline Rodriguez-Valentin 1 , Mariela Rivera 1 , Maridaliz Rodriguez 1 , Mohan Babu 2 , Luis A. Cubano 1 , Huangui Xiong 3 , Guangdi Wang 4 , Lilia Kucheryavykh 5 and Nawal M. Boukli 1 1 Biomedical Proteomics Facility, Department of Microbiology and Immunology, Universidad Central del Caribe, School of Medicine, Bayamon, PR, USA 2 Department of Biochemistry, Research and Innovation Center, University of Regina, Saskatchewan, Canada 3 Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA 4 RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA, USA 5 Department of Biochemistry, Universidad Central del Caribe, School of Medicine, Bayamon, PR, USA Correspondence to: Nawal M. Boukli, email: nawal.boukli@uccaribe.edu Keywords: HIV-1 clades B and C, Gp120, GRP78, quantitative proteomics (tandem mass tag), unfolded protein response (UPR) Received: March 24, 2017     Accepted: June 28, 2017     Published: July 22, 2017 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.