title: HIV-1 Tat inhibits EAAT-2 through AEG-1 upregulation in models of HIV-associated neurocognitive disorder.
abstract: 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.
authors.affiliation: 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.
authors.forename: Xiang
authors.initials: X
authors.lastname: Ye
authors.affiliation: 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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Qiping
authors.initials: Q
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Honghua
authors.initials: H
authors.lastname: Zheng
authors.affiliation: 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.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Qiu
authors.affiliation: 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.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Institute of Laboratory Animal Sciences of Chinese Academy of Medical Science, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Shao
authors.affiliation: 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.
authors.forename: Hui Qin
authors.initials: HQ
authors.lastname: Xing
mesh_terms: D015815:Cell Adhesion Molecules / Q000378:metabolism*; D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D015658:HIV Infections / Q000503:physiopathology* / Q000821:virology; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D008565:Membrane Proteins; D019965:Neurocognitive Disorders / Q000453:epidemiology / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D016601:RNA-Binding Proteins; D015854:Up-Regulation; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000494:pharmacology*
chemical_list: D015815:Cell Adhesion Molecules; D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; C483039:MTDH protein, human; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; C493397:SLC1A2 protein, human; D054322:tat Gene Products, Human Immunodeficiency Virus
keywords: AEG-1; EAAT-2; HIV-1 Tat; HIV-associated neurocognitive disorder; PI3-K