Abstract：
Despite widespread use of combination antiretroviral therapy (cART), there remains a subset of individuals who display cognitive impairment broadly known as HIV-associated neurocognitive disorder (HAND). Interestingly, HIV-infected cells continuously release the HIV-1 protein Tat even in the presence of cART. Persistent exposure to Tat is proposed to increase both neuroinflammation and neurotoxicity. In vitro evidence shows that matrix metalloproteinases (MMPs) are among the neuroinflammatory molecules induced by Tat, which are known to disrupt specialized neuronal extracellular matrix structures called perineuronal nets (PNNs). PNNs predominantly surround parvalbumin interneurons and help to buffer these cells from oxidant stress and to independently increase their excitability. In order to better understand the link between short-term exposure to Tat, neuroinflammation, and PNNs, we explored the direct effects of Tat on glial cells and neurons. Herein, we report that in mixed glial cultures, Tat directly increases the expression of proinflammatory molecules, including MMP-9. Moreover, direct injection of Tat protein into mouse hippocampus increases the expression of astrocyte and microglia markers as well as MMP-9. The number of PNNs is decreased following Tat exposure, followed later by decreased numbers of hippocampal parvalbumin-expressing neurons. In older mice, Tat induced significant increases in the gene expression of proinflammatory molecules including markers of gliosis, MMPs and complement system proteins. Taken together, these data support a direct effect of Tat on glial-derived MMP expression subsequently affecting PNNs and neuronal health, with older mice more susceptible to Tat-induced inflammation.
摘要：
尽管广泛使用联合抗逆转录病毒疗法（cART），仍有一部分个体表现出广泛称为HIV相关神经认知障碍(HAND)的认知障碍.有趣的是,即使在存在cART的情况下，HIV感染的细胞也会持续释放HIV-1蛋白Tat。建议持续暴露于Tat会增加神经炎症和神经毒性。体外证据表明，基质金属蛋白酶（MMPs）是Tat诱导的神经炎分子之一，已知它们会破坏称为神经周网（PNN）的专门的神经元细胞外基质结构。PNN主要围绕小清蛋白中间神经元，并有助于缓冲这些细胞免受氧化应激并独立增加其兴奋性。为了更好地理解短期接触Tat之间的联系，神经炎症，和PNN，我们探讨了Tat对神经胶质细胞和神经元的直接作用。在这里，我们报告说，在混合胶质培养中，Tat直接增加促炎分子的表达，包括MMP-9。此外，小鼠海马直接注射Tat蛋白可增加星形胶质细胞和小胶质细胞标志物以及MMP-9的表达。PNN的数量在Tat暴露后减少，随后海马小清蛋白表达神经元数量减少。在年长的老鼠中，Tat诱导促炎分子的基因表达显着增加，包括神经胶质增生的标志物，MMP和补体系统蛋白。一起来看,这些数据支持Tat对神经胶质来源的MMP表达的直接影响，随后影响PNN和神经元健康，年龄较大的小鼠更容易受到Tat诱导的炎症。
