Kolson D L, Collman R, Hrin R, Balliet J W, Laughlin M, McGann K A, Debouck C, Gonzalez-Scarano F
Department of Neurology, University of Pennsylvania Medical Center, Philadelphia 19104.
J Gen Virol. 1994 Aug;75 ( Pt 8):1927-34. doi: 10.1099/0022-1317-75-8-1927.
Neurological dysfunction in AIDS occurs in the absence of productive infection of neurons, and may involve modulation of neuronal cell function by viral or cellular products released from surrounding infected cells. The human immunodeficiency virus type 1 (HIV-1) trans-activator protein Tat may be one such factor, as it can act as a neurotoxin, induces marked morphological changes in neurons and astrocytes in primary embryonic rodent brain cultures, and is released by certain HIV-1-infected cells. In addition, Tat can alter expression of cellular genes in several non-neuronal cell types. To explore the possibility that Tat may also mediate neuronal dysfunction in AIDS through non-lethal effects on neurons, we determined the trans-activating ability of Tat in human neuronal cells. We generated human neuronal cell lines stably expressing several HIV-1 tat genes, and also tested human neuronal cells exposed to extracellular recombinant Tat protein. Both endogenously expressed Tat as well as exogenous recombinant Tat protein up-regulated HIV-1 long terminal region (LTR)-driven gene expression by several hundred-fold. Only brief exposure to recombinant Tat was necessary and no toxic effects were seen at levels sufficient for trans-activation. Furthermore, Tat significantly enhanced virus expression in neuronal cells transfected with molecular clones of HIV-1. These results show that Tat is trans-activationally active in human neuronal cells, and can be taken up from the extracellular compartment by these cells in a biologically active form. Neurons represent an important potential target for Tat-mediated cellular dysfunction.
艾滋病中的神经功能障碍在神经元无有效感染的情况下发生，可能涉及周围受感染细胞释放的病毒或细胞产物对神经元细胞功能的调节。人类免疫缺陷病毒1型（HIV-1）反式激活蛋白Tat可能就是这样一种因素，因为它可作为一种神经毒素，在原代胚胎啮齿动物脑培养物中诱导神经元和星形胶质细胞发生明显的形态变化，并且由某些HIV-1感染细胞释放。此外，Tat可改变几种非神经元细胞类型中细胞基因的表达。为了探究Tat也可能通过对神经元的非致死性作用介导艾滋病中神经元功能障碍的可能性，我们测定了Tat在人神经元细胞中的反式激活能力。我们构建了稳定表达几种HIV-1 tat基因的人神经元细胞系，并且还检测了暴露于细胞外重组Tat蛋白的人神经元细胞。内源性表达的Tat以及外源性重组Tat蛋白均使HIV-1长末端重复序列（LTR）驱动的基因表达上调数百倍。只需短暂暴露于重组Tat，并且在足以实现反式激活的水平下未观察到毒性作用。此外，Tat显著增强了用HIV-1分子克隆转染的神经元细胞中的病毒表达。这些结果表明，Tat在人神经元细胞中具有反式激活活性，并且可以以生物活性形式从细胞外区室被这些细胞摄取。神经元是Tat介导的细胞功能障碍的一个重要潜在靶点。
