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Establishment of an HTLV-I infection model by using human CRM1-transgenic rats

人CRM1转基因大鼠HTLV-I感染模型的建立

基本信息

批准号：
17590411
负责人：
OHASHI Takashi
金额：
$ 2.3万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590411/
关键词：
HTLV-I Tax ATL CRM1 transgenic rat animal model HTLV-I Animal model

项目摘要

Human T-cell leukemia virus type I (HTLV-I) has been known to cause adult T-cell leukemia (ATL) in infected individuals after a long incubation period, but the in vivo mechanism by which the virus causes the malignant transformation is largely unknown. In order to develop a suitable animal model for the investigation of HTLV-I-related leukemogenesis, in this study, we have examined in vivo proliferation of HTLV-I in rats carrying the human CRM1 (hCRM1) gene, which encodes a viral RNA transporter shown in vitro to be a species specific restriction factor between human and rat. The hCRM1-transgenic (Tg) rats were established from an F344/Slc rat. We have isolated several HTLY-1-infected T cell lines from Tg rats and found that production of Gag by T cells derived from Tg rats were significantly higher than that by wild type (Wt)-derived cells. We next assessed the proliferation of HTLV-I in Tg rats by inoculating HTLV-I-infected T cells. Analysis of plasma pl9 concentration in the infected rats over time did not show significant differences between Tg and Wt rats, although pl9 concentration in Tg rats tended to be higher in the first 4 weeks after infection. We also assessed the tissue distribution of HT LV-I provirus DNA at 1 week after intraperitoneal infection and found that the rate of the virus disseminated to thymus in Tg rats was significantly higher than that in Wt rats. However, we have not detected notable difference in HTLV-I proviral load between the two groups so far. Since we have observed significant enhancement of HTLV-I production in cells derived from Tg rats in vitro, the limited effects of hCRM1 observed in vivo study suggests that HT LV-I-specific immune responses may reduce the enhanced virus production in Tg rats.

已知人类T细胞白血病病毒I型（HTLV-I）在感染个体中经过长时间的潜伏期后会导致成人T细胞白血病（ATL），但病毒导致恶性转化的体内机制在很大程度上是未知的。为了开发一个合适的动物模型的HTLV-I相关的白血病发生的调查，在这项研究中，我们已经研究了在体内增殖HTLV-I在大鼠携带人CRM 1（hCRM 1）基因，该基因编码的病毒RNA转运蛋白在体外被证明是一个种属特异性限制因素之间的人和大鼠。从F344/Slc大鼠建立hCRM 1转基因（Tg）大鼠。我们已经从Tg大鼠中分离出几种HTLY-1感染的T细胞系，并发现来自Tg大鼠的T细胞的Gag产量显著高于野生型（Wt）来源的细胞。接下来，我们通过HTLV-I感染的T细胞评估了Tg大鼠中HTLV-I的增殖。感染大鼠中血浆pl 9浓度随时间的分析未显示Tg和Wt大鼠之间的显著差异，尽管Tg大鼠中的pl 9浓度在感染后的前4周倾向于更高。我们还评估了HTLV-Ⅰ前病毒DNA在腹腔感染后1周的组织分布，发现Tg大鼠的病毒播散到胸腺的比率显著高于Wt大鼠。然而，到目前为止，我们还没有发现两组之间HTLV-Ⅰ前病毒载量的显著差异。由于我们在体外观察到来自Tg大鼠的细胞中HTLV-I产生的显著增强，因此在体内研究中观察到的hCRM 1的有限作用表明，HT LV-I特异性免疫应答可能减少Tg大鼠中增强的病毒产生。