PVC-211 MURINE LEUKEMIA VIRUS--DETERMINANTS OF NEUROPATHOGENICITY

PVC-211 鼠白血病病毒——神经致病性的决定因素

• 批准号: 3752796
• 负责人: S K RUSCETTI
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3752796
• 关键词: Friend virus; disease /disorder model; genetic strain; glycosylation; laboratory rat; murine leukemia virus; neural degeneration; neurotropic virus; tissue /cell culture; vascular endothelium; virus envelope; virus infection mechanism; virus protein; virus receptors

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.

使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 PVC-211小鼠 白血病病毒（MuLV）是FriendMuLV的神经致病性变体， 导致易感小鼠和大鼠的神经退行性疾病。 我们有 先前表明PVC-211 MuLV对 脑毛细血管内皮细胞（BCEC）比Friend MuLV和有 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 负责内皮细胞嗜性，从而导致神经致病性， 位于PVC包膜基因的SU蛋白编码区， 211 MuLV。 为了测试PVC-211 MuLV的BCEC向性的可能性， 结果从一个独特的病毒受体相互作用的BCEC，我们比较了 PVC-211 MuLV和其他MuLV对永久细胞系的感染性 来源于大鼠BCEC的原代培养物。 虽然这种细胞系 表达亲嗜性MuLV受体的高水平mRNA，只有PVC- 211 MuLV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依赖性修饰， 这些细胞。 利用PVC-211 MuLV和 Friend MuLV表明，在N- 其SU包膜蛋白的末端一半负责BCEC PVC-211 MuLV的向性。 因此，PVC-211包膜基因的变化 MuLV使其能够有效地进入中枢神经系统， 感染大脑中的内皮细胞， 受体的 来自耐药动物的BCEC仍然可以被感染 与PVC-211 MuLV在体外，表明耐药性不是在 目标细胞的水平。 PVC的不寻常的内皮细胞向性- 211 MuLV还显示延伸到血管外的内皮细胞。 大脑，使病毒成为基因转移研究的有前途的载体 靶向内皮细胞。