PVC-211 MURINE LEUKEMIA VIRUS--DETERMINANTS OF NEUROPATHOGENICITY

利用啮齿动物模型系统，已经进行了研究，以确定 为什么某些逆转录病毒会导致神经系统疾病。聚氯乙烯-211小鼠 白血病病毒(MuLV)是Friend MuLV的一种神经致病变种 在易感小鼠和大鼠中引起神经退行性疾病。我们有 先前显示，PVC-211MuLV对 脑毛细血管内皮细胞(BCEC)比Friend MuLV和 是病毒的内皮细胞嗜性与其 神经致病性。我们还表明，主要决定因素 负责内皮细胞的趋向性，从而导致神经致病， 定位于PVC膜基因的SU蛋白编码区。 211-LV。测试PVC-211-LV的BCEC取向的可能性 来自BCEC上独特的病毒-受体相互作用的结果，我们比较了 PVC-211MuLV和其他MuLV对永久细胞系的感染性 来源于大鼠BCEC的原代培养。尽管这一细胞系 表达高水平的生态型MuLV受体，只有PVC- 211MuLV能有效地感染这些细胞。进一步的研究表明 F-MuLV和其他MuLV未能有效感染BCEC 由于病毒受体的糖基化修饰 这些细胞。利用聚氯乙烯-211病毒和嵌合病毒的研究 Friend MuLV表明，N-氨基酸中只有两个氨基酸的差异 它的SU包膜蛋白的末端一半负责BCEC 聚氯乙烯-211的取向。因此，聚氯乙烯-211的囊膜基因的变化 MULV使其能够高效地进入中枢神经系统 通过改良的或独特的病毒感染脑内皮细胞 受体。来自抗药性动物的BCEC仍然可能被感染 与PVC-211MuLV共培养，表明抗性不是在 目标单元格的级别。聚氯乙烯不寻常的内皮细胞趋向性- 211MuLV也被显示延伸到血管外的内皮细胞。 大脑，使该病毒成为基因转移研究的有前途的载体 以内皮细胞为靶点。

Using rodent model systems, studies have been carried out to determine why certain retroviruses cause neurological disease. PVC-211 murine leukemia virus (MuLV) is a neuropathogenic variant of Friend MuLV that causes neurodegenerative disease in susceptible mice and rats. We have previously shown that PVC-211 MuLV is significantly more infectious to brain capillary endothelial cells (BCEC) than Friend MuLV and that there is a correlation between endothelial cell tropism of the virus and its neuropathogenicity. We have also shown that the major determinant responsible for endothelial cell tropism, and thus neuropathogenicity, is localized to the SU protein coding region of the envelope gene of PVC- 211 MuLV. To test the possibility that BCEC tropism of PVC-211 MuLV results from a unique virus-receptor interaction on BCEC, we compared the infectivity of PVC-211 MuLV and other MuLVs on a permanent cell line derived from a primary culture of rat BCEC. Although this cell line expresses a high level of mRNA for the ecotropic MuLV receptor, only PVC- 211 MuLV could efficiently infect these cells. Further studies indicated that the failure of F-MuLV and other MuLVs to efficiently infect BCEC was due to a glycosylation-dependent modification of the viral receptor on these cells. Studies utilizing chimeric viruses between PVC-211 MuLV and Friend MuLV showed that as few as two amino acid differences in the N- terminal half of its SU envelope protein were responsible for the BCEC tropism of PVC-211 MuLV. Thus, changes in the envelope gene of PVC-211 MuLV have enabled it to enter the central nervous system by efficiently infecting endothelial cells in the brain via a modified or unique receptor. BCEC derived from resistant animals could still be infected with PVC-211 MuLV in vitro, indicating that resistance was not at the level of the target cell. The unusual endothelial cell tropism of PVC- 211 MuLV was also shown to extend to endothelial cells outside of the brain, making the virus a promising vector for gene transfer studies targeting endothelial cells.