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

Xun Liu,Ankit Shah,Anil Kumar,Peter S Silverstein,Mingui Fu,Mohitkumar R Gangwani

doi:10.1038/srep04450

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.

Highlights

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
The results demonstrated that the PI3K/Akt and p38 MAPK pathways, along with the transcription factors NF-kB, CEBP, and AP-1, are involved in Nef-induced CCL5 production in astrocytes
The direct effects of CNS infection with HIV-1 are due to the neurotoxicity of HIV-1 and HIV-1 proteins, including gp[120], Tat and Nef, whereas indirect neurotoxicity is caused by the secretion of toxic mediators such as quinolinic acid and arachidonic acid metabolites, as well as pro-inflammatory cytokines which are released by microglia or astrocytes that are either infected with HIV-1 or exposed to HIV-1 proteins[3,4,5]

Summary

Introduction

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. Specific siRNAs demonstrated that the Akt, p38MAPK, NF-kB, 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-kB, CEBP, and AP-1, are involved in Nef-induced CCL5 production in astrocytes. 70% of the brain is comprised of astrocytes, and these cells are subject to a low level of productive infection as well as non-productive infection with HIV-16,7 As these cells are responsible for maintaining homeostasis in the brain, they play a major role in mediating the neurotoxic effects of HIV-1 infection of the CNS. Results obtained with the SIV model of HIV/AIDS demonstrated that a functional nef gene plays a role in maintaining high viral loads and maximal pathogenic potential early in infection[13]. A clone of SIVmac[239] which was deleted in nef, vpr and a negative regulatory element, proved to be pathogenic in adult macaques when such determinations were made several years after inoculation[15]

Methods

Results

Conclusion