HIV-1 Tat inhibits EAAT-2 through AEG-1 upregulation in models of HIV-associated neurocognitive disorder

Xiang Ye, Yu Zhang, Qiping Xu, Honghua Zheng, Xiaoyan Wu, Jinhua Qiu, Zhou Zhang, Wei Wang, Yiming Shao and Hui Qin Xing _

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Oncotarget. 2017; 8:39922-39934. https://doi.org/10.18632/oncotarget.16485

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Xiang Ye1,*, Yu Zhang1,*, Qiping Xu1, Honghua Zheng1, Xiaoyan Wu1, Jinhua Qiu1, Zhou Zhang2, Wei Wang3, Yiming Shao2 and Hui Qin Xing1

1 Department of Pathology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Basic Medicine, Medical College, Xiamen University, Xiamen, Fujian, China

2 State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China

3 Institute of Laboratory Animal Sciences of Chinese Academy of Medical Science, Beijing, China

* These authors have contributed equally to this article

Correspondence to:

Huiqin Xing, email:

Keywords: AEG-1; EAAT-2; HIV-1 Tat; HIV-associated neurocognitive disorder; PI3-K

Received: August 02, 2016 Accepted: January 23, 2017 Published: March 22, 2017


During HIV-associated neurocognitive disorder (HAND), decreasing in excitatory amino acid transporter 2 (EAAT-2) in astrocyte plasma membranes leads to elevated levels of extracellular glutamate and, in turn, neuronal apoptosis. We used immunohistochemistry, western blot, qRT-PCR, and RNA interference to elucidate the molecular mechanisms underlying the decreased EAAT-2 expression during HAND at the tissue and cellular levels. We used simian immunodeficiency virus-human immunodeficiency virus chimeric virus (SHIV)-infected macaques as an in vivo model of HAND. Our results show that EAAT-2 expression was decreased in the cerebral cortex, while AEG-1 expression was increased, and the expression levels of these proteins were negatively correlated. In vitro analyses showed that HIV-1 Tat inhibited EAAT-2 expression by inducing overexpression of AEG-1. More specifically, HIV-1 Tat increased AEG-1 expression via the PI3-K signaling pathway, while increasing EAAT-2 inhibition by YinYan-1 (YY-1) via the NF-κB signaling pathway. These results warrant testing AEG-1 as a potential therapeutic target for treating HAND.

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