Abstract
The prevalence of HIV-associated neurocognitive disorders (HAND) remains high in patients infected with HIV-1. The production of pro-inflammatory cytokines by astrocytes/microglia exposed to viral proteins is thought to be one of the mechanisms leading to HIV-1- mediated neurotoxicity. In the present study we examined the effects of Nef on CCL5 induction in astrocytes. The results demonstrate that CCL5 is significantly induced in Nef-transfected SVGA astrocytes. To determine the mechanisms responsible for the increased CCL5 caused by Nef, we employed siRNA and chemical antagonists. Antagonists of NF-κB, PI3K, and p38 significantly reduced the expression levels of CCL5 induced by Nef transfection. Furthermore, specific siRNAs demonstrated that the Akt, p38MAPK, NF-κB, CEBP, and AP-1 pathways play a role in Nef-mediated CCL5 expression. The results demonstrated that the PI3K/Akt and p38 MAPK pathways, along with the transcription factors NF-κB, CEBP, and AP-1, are involved in Nef-induced CCL5 production in astrocytes.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Astrocytes / metabolism
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Astrocytes / pathology
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CCAAT-Enhancer-Binding Proteins / genetics*
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CCAAT-Enhancer-Binding Proteins / metabolism
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Cell Line
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Chemokine CCL5 / genetics*
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Chemokine CCL5 / metabolism
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Cognition Disorders / complications
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Cognition Disorders / genetics
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Cognition Disorders / pathology
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Cognition Disorders / virology
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Elafin / antagonists & inhibitors
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Gene Expression Regulation, Viral
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HIV Infections / complications
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HIV Infections / genetics*
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HIV Infections / virology
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HIV-1 / genetics*
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HIV-1 / pathogenicity
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NF-kappa B / antagonists & inhibitors
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Neurotoxicity Syndromes / complications
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Neurotoxicity Syndromes / genetics
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Neurotoxicity Syndromes / pathology
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Oncogene Protein v-akt / metabolism
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Signal Transduction
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Transcription Factor AP-1 / genetics*
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Transcription Factor AP-1 / metabolism
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nef Gene Products, Human Immunodeficiency Virus / genetics*
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nef Gene Products, Human Immunodeficiency Virus / metabolism
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
Substances
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CCAAT-Enhancer-Binding Proteins
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CCL5 protein, human
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CEBPA protein, human
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Chemokine CCL5
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Elafin
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NF-kappa B
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PI3 protein, human
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Transcription Factor AP-1
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nef Gene Products, Human Immunodeficiency Virus
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nef protein, Human immunodeficiency virus 1
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Oncogene Protein v-akt
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p38 Mitogen-Activated Protein Kinases