HIV-1感染激活中枢免疫细胞，释放病毒颗粒和炎症因子致神经元损伤，是引起HIV相关神经认知障碍（HAND）的主要机制，而其中起重要作用的包膜蛋白gp120致小胶质细胞持续炎症反应的机制尚不清楚。我们和他人研究已证实gp120可致大鼠空间记忆障碍及小胶质细胞炎症，近期我们观察自噬在gp120致小胶质细胞炎症中的变化，发现早期自噬关键蛋白p62降低，对炎症有保护作用；而晚期p62升高伴大量炎症因子释放，促炎症。推测这种早、晚期截然不同的炎症反应可能由不同水平的p62致差异调控下游信号分子而实现。为验证此假说，本研究拟使用人源CHME5小胶质细胞、CHME5和原代神经元细胞共培养及大鼠动物模型，从p62-Nrf2、 p62-NF-kB角度，寻找p62下游关键信号分子靶点并加以阻断，探究小胶质细胞早、晚期反应中p62水平变化引起截然不同炎症变化的分子机制，为HAND的防治提供全新的视角和新策略。

HIV-1 infection activates central immune cells and releases virual particles and inflammatory factors to cause neuronal damage, which is the main mechanism of HIV-1 associated neurocognitive disorders(HAND). Although HIV gp120 is a potent neurotoxin, the exact mechanism by which envelope protein gp120 causes persistent microglial inflammatory response remains unknown. We and others have reported that HIV gp120 can induce microglial inflammation and cause impairment of spatial learning and memory in Spraque Dawley(SD) rats. Significantly, our recent data demonstrated that autophagy related protein p62 decreased during the early stage of interaction between HIV gp120 and microglia cells, while p62 markedly increased accompaning with massive release of inflammatory factors was observed in the late stage of the interaction. Therefore, we hypothesize that p62 decreased in the early stage of interaction between HIV gp120 and microglia cells exerts a protective effect for inflammation, and p62 markedly increased in the late stage leads to neuroinflammation. We also hypothesize that autophagy related protein p62 triggers different downstream signal pathways in the early stage versus the late stage of the interaction between HIV gp120 and microglia cells. To test thesehypotheses, human CHME5 microglia cells, co-culture of CHME5 microglia cells and primary neurons and SD rats will be used as animal models, We will conduct in vitro and in vivo experiments to study key signal molecules that potentially link p62-Nrf2 and p62-NF-kB and gp120-triggered autophagy downstream pathways. Specific inhibitors of the key signal molecules will be used to probe their functions. Finally, we will study the molecular mechanisms underlying autophagy related protein p62 and microglial neuroinflammation in the early stage versus late stage of gp120 challenge. Our results will provide critical insights to the understanding of HAND pathogenesis and to the development of preventive and therapeutic interventions of HAND.