Development of Pharmacokinetic and Safety Assessment of in vivo Virus Infection and Vaccine Therapy

阐明病毒感染的器官嗜性机制在基因和疫苗治疗中具有重要意义。本研究选择已知的脊髓灰质炎病原体脊髓灰质炎病毒作为模型病毒，用于疫苗治疗的安全性评价和基于药代动力学分析的体内病毒感染预测。携带人类脊髓灰质炎病毒受体(PVR)基因的转基因(TG)小鼠对静脉接种脊髓灰质炎病毒(IV)易感，已用于体内感染研究。为了了解PVR对静脉接种脊髓灰质炎病毒的组织分布和血脑屏障通透性的影响，我们在Tg小鼠和非Tg小鼠之间对这些过程进行了研究和比较。脊髓灰质炎病毒在转基因小鼠体内的分布与非转基因小鼠相似，提示脊髓灰质炎病毒在组织中的分布不依赖于转基因的PVR。脊髓灰质炎病毒转移到中枢神经系统后，无论是强毒株还是弱毒株，病毒似乎都以大约0.2ul/min/g脑的恒定速度累积。当病毒接种到非转基因小鼠身上时，也观察到了类似的现象。这些数据表明，脊髓灰质炎病毒以相当高的速度渗透到血脑屏障中，与PVR和VERUS株无关。如果在人类中也是如此，包括沙宾疫苗株在内的循环中的脊髓灰质炎病毒很容易入侵人的中枢神经系统。除PVR之外的一些分子可能参与了脊髓灰质炎病毒的血脑屏障通透性。

It is significantly important subjict to elucidate the mechanism of organ tropism of virus infection in gene and vaccine therapy. In the present study, poliovirus, known to be the causative agent of poliomyelitis, has been selected as a model virus to develop the safety assesement of vaccine therapy and to predict the in vivo virus infection in the body based on pharmacokinetic analysis. The transgenic (Tg) mice carrying the human gene for poliovirus receptor (PVR), which is susceptible to intraven ously (IV) -inoculated poliovirus, has been used for the in vivo enfection studies. To know cotribution of PVR to tissue distribution and BBB permeability of IV-inoculated polioviruses, these processes were investigated and compared between the Tg mice and non-Tg mice. Distribution profile of IV-inoculated poliovirus in various tissues of the Tg mice is similar to that in non-Tg mice, suggesting that tissue distribution of IV-inoculated virus is independent of the transgene for PVR.Amount of poliovirus transfered to the CNS demonstrates an existence of specific invasion pathway for the virus to the CNS.The viruses, regardless of whether the virulent and attenuated strain, seem to accumulate at a constant rate of approximately 0.2ul/min/g brain. Similar phenomena were observed when the viruses were inoculated into non-Tg mice. These data suggest that polioviruses permeate the BBB at a fairly high rate, independently of PVR and verus strains. If it is also true in humans, circulating poliovirus including the Sabin vaccine strains easily invade the human CNS.Some molecules other than PVR may be involved in the BBB permeability of poliovirus.