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Sci Rep. 2016 Jan 7;6:18929. doi: 10.1038/srep18929.

HIV-1 gp120 induces type-1 programmed cell death through ER stress employing IRE1α, JNK and AP-1 pathway.

Author information

1
Division of Pharmacology and Toxicology, School of Pharmacy, Kansas City, MO 64108.
2
Department of Mathematics and Statistics, University of Missouri-Kansas City, Kansas City, MO 64108.

Abstract

The ER stress-mediated apoptosis has been implicated in several neurodegenerative diseases; however, its role in HIV/neuroAIDS remains largely unexplored. The present study was undertaken to assess the involvement and detailed mechanism of IRE1α pathway in HIV-1 gp120-mediated ER stress and its possible involvement in cell death. Various signaling molecules for IRE1α pathway were assessed using SVGA cells, primary astrocytes and gp120 transgenic mice, which demonstrated gp120-mediated increase in phosphorylated JNK, XBP-1 and AP-1 leading to upregulation of CHOP. Furthermore, HIV-1 gp120-mediated activation of IRE1α also increased XBP-1 splicing. The functional consequence of gp120-mediated ER stress was determined via assessment of gp120-mediated cell death using PI staining and MTT assay. The gp120-mediated cell death also involved caspase-9/caspase-3-mediated apoptosis. These findings were confirmed with the help of specific siRNA for IRE1α, JNK, AP-1, BiP and CHOP showing significant reduction in gp120-mediated CHOP expression. Additionally, silencing all the intermediates also reduced the gp120-mediated cell death and caspase-9/caspase-3 activation at differential levels. This study provides ER-stress as a novel therapeutic target in the management of gp120-mediated cell death and possibly in the treatment of neuroAIDS.

PMID:
26740125
PMCID:
PMC4703964
DOI:
10.1038/srep18929
[Indexed for MEDLINE]
Free PMC Article

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