Impact of Opiate–HIV-1 Interactions on Neurotoxic Signaling |
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Authors: | Kurt F Hauser Nazira El-Hage Shreya Buch Avindra Nath William R Tyor Annadora J Bruce-Keller Pamela E Knapp |
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Institution: | (1) Department of Anatomy and Neurobiology, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY 40536-0298, USA;(2) Spinal Cord and Brain Injury Research Center (SCoBIRC), University of Kentucky Medical Center, Lexington, KY 40536, USA;(3) Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA;(4) Department of Neurscience, Medical University of South Carolina, Charleston, SC 29425, USA |
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Abstract: | Opiate drug abuse exacerbates the pathogenesis of human immunodeficiency virus-1 (HIV-1) in the central nervous system through
direct actions on glia and neurons. Opiate abuse causes widespread disruption of astroglial and microglial function, and significant
increases in astroglial-derived proinflammatory cytokines and chemokines, which likely contributes to neuronal dysfunction,
death, and HIV encephalitis. Neurons are also directly affected by opiate–HIV-1 interactions. HIV-1 and the viral proteins
gp120 and Tat activate multiple caspase-dependent and caspase-independent proapoptotic pathways in neurons involving phosphatidylinositol
3-kinase (PI3 kinase)/Akt, as well as p38, c-Jun N-terminal kinase (JNK) and/or other mitogen-activated protein kinases (MAPKs).
Opiates appear to decrease the threshold for HIV-1-mediated neurotoxicity by sending convergent signals that exacerbate proapoptotic
events induced by viral and cellular toxic products. The synergistic proinflammatory and neurotoxic effects of opiate drugs
on glia and neurons are largely mediated through μ opioid receptors, which are expressed by subpopulations of astroglia, microglia,
and neurons. Opiate abuse intrinsically modifies the host response to HIV-1. Identification of how this occurs is providing
considerable insight toward understanding the mechanisms underlying HIV-1-associated dementia. |
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Keywords: | AIDS μ -opioid receptors neurons astroglia microglia neuroimmunology monocyte chemoattractant protein-1 (MCP-1/CCL2) apoptosis p38 mitogen-activated protein kinase (MAPK) c-Jun N-terminal kinase (JNK) caspase-3 |
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