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However, the prevalence of more subtle forms of neurocognitive dysfunction continues to escalate. Recently, endoplasmic reticulum (ER) stress has been linked to many neurological diseases; yet, its role in HIV\/neuroAIDS remains largely unexplored. Furthermore, upregulation of astrocyte elevated gene-1 (<jats:italic>AEG-1<\/jats:italic>), a novel HIV-1 inducible gene, along with ER stress markers in a Huntington\u2019s disease model, suggests a possible role in HIV-associated ER stress. The current study is focused on unfolded protein responses (UPRs) and AEG-1 regulation in primary human astrocytes exposed to HIV-associated neurocognitive disorders (HAND)-relevant stimuli (HIV-1 virions, inflammation and ARV drugs). Interleukin (IL)-1<jats:italic>\u03b2<\/jats:italic> and the nucleoside reverse transcriptase inhibitor abacavir upregulated expression of ER stress markers in human astrocytes, including binding immunoglobulin protein (BiP), C\/EBP homologous protein (CHOP), and calnexin. In addition, IL-1<jats:italic>\u03b2<\/jats:italic> activated all three well-known UPR pathways: protein kinase RNA-like ER kinase (PERK); activating transcription factor 6 (ATF-6); and inositol-requiring enzyme 1<jats:italic>\u03b1<\/jats:italic> (IRE1<jats:italic>\u03b1<\/jats:italic>). AEG-1 upregulation correlated to ER stress and demonstrated astrocyte AEG-1 interaction with the calcium-binding chaperone, calnexin. IL-1<jats:italic>\u03b2<\/jats:italic> and abacavir enhanced intracellular calcium signaling in astrocytes in the absence of extracellular calcium, illustrating ER-associated calcium release. Alternatively, calcium evoked in response to HAND-relevant stimuli led to mitochondrial permeability transition pore (mPTP) opening in human astrocytes. Importantly, IL-1<jats:italic>\u03b2<\/jats:italic>- and abacavir-induced UPR and mPTP opening were inhibited by the intracellular calcium chelation, indicating the critical role of calcium signaling in HAND-relevant ER stress in astrocytes. In summary, our study highlights that ARV drugs and IL-1<jats:italic>\u03b2<\/jats:italic> induced UPR, AEG-1 expression, intracellular calcium, and mitochondrial depolarization in astrocytes. This study uncovers astrocyte ER stress as a novel therapeutic target in the management of HIV-1-associated neurotoxicity and possibly in the treatment of neuroAIDS.<\/jats:p>","DOI":"10.1038\/cddiscovery.2017.61","type":"journal-article","created":{"date-parts":[[2017,12,4]],"date-time":"2017-12-04T05:03:26Z","timestamp":1512363806000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["HIV-1-associated inflammation and antiretroviral therapy regulate astrocyte endoplasmic reticulum stress responses"],"prefix":"10.1038","volume":"3","author":[{"given":"Shruthi","family":"Nooka","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anuja","family":"Ghorpade","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,12,4]]},"reference":[{"key":"BFcddiscovery201761_CR1","first-page":"54","volume":"17","author":"D Elbirt","year":"2015","unstructured":"Elbirt D, Mahlab-Guri K, Bezalel-Rosenberg S, Gill H, Attali M, Asher I . 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