Abstract
Astrocyte elevated gene-1 (AEG-1), a novel human immunodeficiency virus (HIV)-1 and tumor necrosis factor (TNF)-α-inducible oncogene, has generated significant interest in the field of cancer research as a therapeutic target for many metastatic aggressive tumors. However, little is known about its role in astrocyte responses during HIV-1 central nervous system (CNS) infection and whether it contributes toward the development of HIV-associated neurocognitive disorders (HAND). Therefore, in this study, we investigated changes in AEG-1 CNS expression in HIV-1-infected brain tissues and elucidated a potential mechanism of AEG-1-mediated regulation of HAND. Immunoblotting and immunohistochemical analyses of HIV-1 seropositive and HIV-1 encephalitic human brain tissues revealed significantly elevated levels of AEG-1 protein. Immunohistochemical analyses of HIV-1 Tat transgenic mouse brain tissues also showed a marked increase in AEG-1 staining. Similar to in vivo observations, cultured astrocytes expressing HIV-1 Tat also revealed AEG-1 and cytokine up-regulation. Astrocytes treated with HAND-relevant stimuli, TNF-α, interleukin (IL)-1β, and HIV-1, also significantly induced AEG-1 expression and nuclear translocation via activation of the nuclear factor (NF)-κB pathway. Co-immunoprecipitation studies demonstrated IL-1β- or TNF-α-induced AEG-1 interaction with NF-κB p65 subunit. AEG-1 knockdown decreased NF-κB activation, nuclear translocation, and transcriptional output in TNF-α-treated astrocytes. Moreover, IL-1β treatment of AEG-1-overexpressing astrocytes significantly lowered expression of excitatory amino acid transporter 2, increased expression of excitatory amino acid transporter 2 repressor ying yang 1, and reduced glutamate clearance, a major transducer of excitotoxic neuronal damage. Findings from this study identify a novel transcriptional co-factor function of AEG-1 and further implicate AEG-1 in HAND-associated neuroinflammation.
Highlights
Role of Astrocyte elevated gene-1 (AEG-1), an human immunodeficiency virus (HIV)-1 neuropathology-associated gene, in astrocytes is unclear
HIV-1 central nervous system (CNS) Infection Induces AEG-1 Expression in the Brain— AEG-1 was originally identified as an HIV-1- and tumor necrosis factor (TNF)-␣-inducible transcript in human astrocytes [8], its expression in the brain of HIV-1ϩ and HIV-1 encephalitic (HIVE) individuals has not been examined
AEG-1 immunostaining demonstrated AEG-1 induction and co-localization with glial fibrillary acidic protein (GFAP) positive astrocytes in HIV-1ϩ and HIVE brain tissues compared with control (Fig. 1, D1–D3)
Summary
Role of AEG-1, an HIV-1 neuropathology-associated gene, in astrocytes is unclear. Results: AEG-1 regulates astrocyte NF-B activation and nuclear translocation, increases YY1 expression, and decreases EAAT2 expression and glutamate clearance. HAND is associated with the accumulation of infected and/or activated macrophages/microglia in the CNS that secrete pro-inflammatory cytokines, such as IL-1 and TNF-␣, chemokines, infectious virions, and potentially neurotoxic viral proteins. These HAND-relevant stimuli can affect neural function and survival by producing excitotoxic damage [6, 7]. Upon exposure to HAND-relevant factors, such as IL-1, TNF-␣, and/or HIV-1, astrocytes initiate multiple autocrine and paracrine inflammatory signaling nodes, leading to elevated production of cytokines and chemokines These factors can enhance immune cell ingress across the blood-brain barrier, thereby contributing toward immune activation. We assessed the role of AEG-1 in astrocyte-mediated neurotoxicity and neuroinflammation in response to HIV-1 neuroinvasion and discuss the implications for HIV-1 CNS infection
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