Buzy J M, Lindstrom L M, Zink M C, Clements J E
Agency for International Development, USAID, Arlington, Virginia 22209, USA.
Virology. 1995 Jul 10;210(2):361-71. doi: 10.1006/viro.1995.1352.
HIV-1 infection of the CNS plays a direct role in the pathogenesis of AIDS dementia that frequently accompanies systemic AIDS. Both adult and pediatric AIDS are characterized by a high proportion of CNS disease. However, the pathogenic mechanisms responsible for AIDS dementia are not understood. A transgenic mouse model using the LTRs of two CNS-derived strains of HIV-1 (HIV-1JR-CSF and HIV-1JR-FL) has been developed to study HIV-1 gene expression in vivo. Analyses of expression in adult transgenic mice revealed expression in neurons in the CNS (J. R. Corboy, J. M. Buzy, M. C. Zink, and J. E. Clement, Science 258, 1804-1808, 1992). In this study, developmental analyses of HIV-1-directed gene expression in embryonic and newborn transgenic mice derived from the above lines revealed strikingly different levels and patterns of expression in the CNS and spinal cord compared with adult mice. Increased expression was observed in the newborn brain compared to the adult, and the neuroanatomical pattern of expression was markedly different than that observed in adult brain. Transient expression was detected in the dorsal root ganglia and spinal cord in embryos and newborns up to Day 14. In contrast to the expression in neurons in adult CNS, HIV-1-directed gene expression in the newborn brain was observed in neurons, endothelial cells, and macrophages. This difference in expression during development probably reflects temporally regulated cellular transcription factors in the CNS. This transgenic model suggests that HIV-1 replication in the CNS may use cellular transcription factors different from those in nonneural tissues. Studies are in progress to identify cellular transcription factors that may be responsible for the differential expression of the LTRs.
中枢神经系统的HIV-1感染在常常伴随系统性艾滋病的艾滋病痴呆症发病机制中起直接作用。成人和儿童艾滋病的特征均为中枢神经系统疾病比例很高。然而，艾滋病痴呆症的致病机制尚不清楚。已开发出一种使用两种源自中枢神经系统的HIV-1毒株（HIV-1JR-CSF和HIV-1JR-FL）的长末端重复序列的转基因小鼠模型，以研究HIV-1在体内的基因表达。对成年转基因小鼠表达情况的分析显示在中枢神经系统的神经元中有表达（J.R. 科尔博伊、J.M. 布齐、M.C. 津克和J.E. 克莱门特，《科学》258, 1804 - 1808, 1992）。在本研究中，对源自上述品系的胚胎和新生转基因小鼠中HIV-1指导的基因表达进行的发育分析显示，与成年小鼠相比，中枢神经系统和脊髓中的表达水平和模式存在显著差异。与成年小鼠相比，在新生小鼠脑中观察到表达增加，并且表达的神经解剖学模式与成年脑中观察到的明显不同。在胚胎和出生至第14天的新生小鼠的背根神经节和脊髓中检测到瞬时表达。与成年中枢神经系统神经元中的表达不同，在新生小鼠脑中，HIV-1指导的基因表达在神经元、内皮细胞和巨噬细胞中均有观察到。发育过程中这种表达差异可能反映了中枢神经系统中受时间调控的细胞转录因子。这种转基因模型表明，HIV-1在中枢神经系统中的复制可能使用与非神经组织中不同的细胞转录因子。正在进行研究以鉴定可能负责长末端重复序列差异表达的细胞转录因子。
