Roberts Eleanor S, Zandonatti Michelle A, Watry Debbie D, Madden Lisa J, Henriksen Steven J, Taffe Michael A, Fox Howard S
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, USA.
Am J Pathol. 2003 Jun;162(6):2041-57. doi: 10.1016/S0002-9440(10)64336-2.
The etiology of the central nervous system (CNS) alterations after human immunodeficiency virus (HIV) infection, such as dementia and encephalitis, remains unknown. We have used microarray analysis in a monkey model of neuroAIDS to identify 98 genes, many previously unrecognized in lentiviral CNS pathogenesis, whose expression is significantly up-regulated in the frontal lobe of simian immunodeficiency virus-infected brains. Further, through immunohistochemical illumination, distinct classes of genes were found whose protein products localized to infiltrating macrophages, endothelial cells and resident glia, such as CD163, Glut5, and ISG15. In addition we found proteins induced in cortical neurons (ie, cyclin D3, tissue transglutaminase, alpha1-antichymotrypsin, and STAT1), which have not previously been described as participating in simian immunodeficiency virus or HIV-related CNS pathology. This molecular phenotyping in the infected brains revealed pathways promoting entry of macrophages into the brain and their subsequent detrimental effects on neurons. These data support the hypothesis that in HIV-induced CNS disease products of activated macrophages and astrocytes lead to CNS dysfunction by directly damaging neurons, as well as by induction of altered gene and protein expression profiles in neurons themselves which are deleterious to their function.
人类免疫缺陷病毒（HIV）感染后中枢神经系统（CNS）改变（如痴呆和脑炎）的病因仍不清楚。我们在神经艾滋病的猴子模型中使用微阵列分析来鉴定98个基因，其中许多基因在慢病毒CNS发病机制中以前未被识别，其表达在感染猿猴免疫缺陷病毒的大脑额叶中显著上调。此外，通过免疫组织化学研究，发现了不同类别的基因，其蛋白质产物定位于浸润的巨噬细胞、内皮细胞和常驻神经胶质细胞，如CD163、Glut5和ISG15。此外，我们还发现了在皮质神经元中诱导产生的蛋白质（即细胞周期蛋白D3、组织转谷氨酰胺酶、α1-抗糜蛋白酶和信号转导和转录激活因子1），这些蛋白质以前未被描述为参与猿猴免疫缺陷病毒或HIV相关的CNS病理学。感染大脑中的这种分子表型揭示了促进巨噬细胞进入大脑及其随后对神经元产生有害影响的途径。这些数据支持这样的假设，即在HIV诱导的CNS疾病中，活化的巨噬细胞和星形胶质细胞的产物通过直接损伤神经元以及通过诱导神经元自身基因和蛋白质表达谱的改变（这对其功能有害）导致CNS功能障碍。
