星形胶质细胞EAAT-2表达低下是导致HIV相关性痴呆（HAD）中胞外谷氨酸浓度过高诱导神经元凋亡的关键因素，然而其机制尚未阐明。我们发现HIV-1Tat可上调AEG-1，下调EAAT-2表达，并且AEG-1过表达的小鼠星形胶质细胞株中p38MAPK高度磷酸化；HIV-1Tat可使小胶质细胞产生过量IL-1β进而下调EAAT-2表达。由此我们推测HIV-1Tat至少通过以下两种机制下调EAAT-2表达，参与HAD的发生：①HIV-1Tat上调AEG-1表达，进而通过p38-MAPK等信号通路下调EAAT-2表达。②HIV-1Tat通过活化小胶质细胞释放过量的IL-1β间接调节EAAT-2表达。本项目拟从SHIV感染恒河猴动物实验、临床尸检标本分析、细胞模型三个层面，使用激光纤维切割、ChIP等技术，阐明HIV-1Tat抑制EAAT-2表达的分子机制，确定其调控的信号分子网络。

With the introduction of highly active anti-retroviral therapy has been successful to reduce progression of acquired immunodeficiency syndrome (AIDS), the lifespan of human immunodeficiency virus (HIV) carriers has been dramatically elongated. However, this also leads to an increased incidence of HIV-associated dementia (HAD). Our previous study prompts that decreased excitatory amino acid transporter 2 (EAAT-2) on the astrocytes accompanied with high levels of glutamate in the synaptic cleft is a key factor responsible for neuronal damage in the process of HAD. However, the underlying molecular mechanism remains unclear. In our preliminary study, we found that HIV-1Tat can upregulate the expression of the astrocyte elevated gene-1 (AEG-1) and downregulate EAAT-2 expression. In addition, we found that p38MAPK was highly phosphorylate upon overexpression of AEG-1 in mouse astrocytes. Furthermore, HIV-1Tat treatments resulted in excessive interleukin-lβ (IL-1β) generation in microglia. Thus, we speculate that HIV-1Tat downregulates EAAT-2 expression through at least two mechanisms in HAD: on one hand, HIV-1Tat may increase astrocyte AEG-1 expression and thus downregulate the expression of EAAT-2 through the p38-MAPK signaling pathway. On the other hand, HIV-1Tat may activate microglia to release excessive IL-1β, resulting in the downregulation of EAAT-2. Here, We will employ laser microdissection, ChIP, and other techniques to elucidate the molecular signaling networks involved in HIV-1Tat inhibitting EAAT-2 expression through AEG-1 and/or IL-1β, using SHIV infected macaque, clinical autopsy specimen and primary cultured astrocyte models. These studies will not only strengthen our understanding of the pathogenesis of HAD, but also identify new molecular targets for HAD treatment.