title: HIV-1 Nef induces CCL5 production in astrocytes through p38-MAPK and PI3K/Akt pathway and utilizes NF-kB, CEBP and AP-1 transcription factors.
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.
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy.
authors.forename: Xun
authors.initials: X
authors.lastname: Liu
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy.
authors.forename: Ankit
authors.initials: A
authors.lastname: Shah
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy.
authors.forename: Mohitkumar R
authors.initials: MR
authors.lastname: Gangwani
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Silverstein
authors.affiliation: Department of Basic Medical Science, School of Medicine, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108.
authors.forename: Mingui
authors.initials: M
authors.lastname: Fu
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy.
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
mesh_terms: D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D018946:Chemokine CCL5 / Q000235:genetics* / Q000378:metabolism; D003072:Cognition Disorders / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000821:virology; D053492:Elafin / Q000037:antagonists & inhibitors; D015967:Gene Expression Regulation, Viral; D015658:HIV Infections / Q000150:complications / Q000235:genetics* / Q000821:virology; D015497:HIV-1 / Q000235:genetics* / Q000472:pathogenicity; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D020258:Neurotoxicity Syndromes / Q000150:complications / Q000235:genetics / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics* / Q000378:metabolism; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C483024:CCL5 protein, human; C515848:CEBPA protein, human; D018946:Chemokine CCL5; D053492:Elafin; D016328:NF-kappa B; C506806:PI3 protein, human; D018808:Transcription Factor AP-1; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; D051058:Oncogene Protein v-akt; D048051:p38 Mitogen-Activated Protein Kinases