Interleukin-1β and Abacavir Induce Astrocyte Endoplasmic Reticulum Stress During HIV-1-Associated Neurocognitive Disorders
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Purpose: Globally 69% of HIV-1-positive individuals suffer from HIV-1-associated neurocognitive disorders (HAND) despite effective anti-retroviral therapy (ART). Persistent glial-mediated inflammation, BBB disruption, increased oxidative stress, and viral protein expression together lead to HIV-1 disease progression. ARV drugs, while successfully controlling viral load, likely induce cellular stress responses, oxidative stress, inflammation, and mitochondrial damage. Recently, endoplasmic reticulum (ER) stress has been linked to many neurological diseases, including HAND. Astrocyte elevated gene (AEG)-1, a HIV-1 inducible gene, upregulation in Huntington’s disease model along with ER stress markers, recommends its possible role in HIV-1/ART triggered ER stress. We hypothesize that HAND-relevant inflammatory stimuli and ARV drugs induce astrocyte ER stress and AEG-1 expression that further mediates cellular stress responses in post-ART HAND. Materials and Methods: Cultured human astrocytes were treated with HIV-1DJV, interleukin (IL)-1β and ARV drugs. Astrocytes were transfected with GCaMP6s plasmid. ER stress markers gene expression and protein levels were determined by RT-PCR, western blot analysis and immunocytochemistry. Confocal imaging and mPTP assay was also performed. Results: HIV-1, IL-1β and ARV drugs abacavir and lamivudine, upregulated ER stress markers, and activated unfolded protein response (UPR) pathways i.e., PERK, ATF6, and IRE1α in astrocytes. IL-1β and abacavir treated astrocytes indicated phosphorylation of eIF2α. ARV drugs and ER stress compounds induced astrocyte AEG-1 levels that correlated to PERK and BiP expression. Intracellular calcium signaling changes in response to IL-1β and abacavir were observed in astrocytes transfected with a genetically encoded calcium indicator, GCaMP6s. IL-1β and abacavir also increased calnexin levels in astrocytes. Further, confocal analysis and mPTP assay showed AEG-1 colocalization with calnexin and mitochondrial damage with ER stress. Conclusions: In summary, our study highlights that ARV drugs and IL-1β induced AEG-1 expression, ER stress, cellular calcium overload, and mitochondrial damage in astrocytes. Therefore, identifying novel mechanisms mediated by astrocytes via ER stress and UPR signaling may have broader implications in neuroAIDS management.