Human immunodeficiency virus-1 (HIV-1)-associated neurodegenerative disorder (HAND) is frequently reported in HIV-infected individuals. The gp120 envelope viral protein has been implicated in the pathogenesis of HAND in HIV-1-infected patients; however, its pathogenic mechanism remains unclear. In this study, we first overexpressed gp120 proteins in pc12 cells and used PI staining, a CCK8 assay, a TUNEL assay, and caspase-9/caspase-3-induced apoptosis to ascertain the mediated cell death. Subsequently, the gp120-overexpressed cells were subjected to RNA transcriptomics and mass spectrometry. The obtained results were integrated and validated using a quantitative polymerase chain reaction (qPCR) and the postmortem brain samples with HIV-associated dementia were analyzed against the normal control (using the GSE35864 data set on gene ontology omnibus repository). Upon the integration of the RNA transcriptomic and proteomic results, 78 upregulated genes were revealed. , , , , and were the top five upregulated genes. Upon the analysis of the GSE35864 data set, the results indicate that was upregulated in HIV-associated dementia in comparison to the normal control. Moreover, the protein expression of was significantly higher in the gp120 transfected group compared to the normal control and decreased significantly upon inhibition using Roscovitine (a known inhibitor). Taken together, our results provide a possible molecular signature of the neurological impairment secondary to HIV glycoprotein 120.