Molecular mechanism of the persistent infection of human T-cell leukemia virus type 1

人T细胞白血病病毒1型持续感染的分子机制

基本信息

批准号：
12670277
负责人：
FUJII Masahiro
金额：
$ 2.11万
依托单位：
Niigata University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670277/
关键词：
HTLV-1 Virus adult T-cell leukemia oncogenesis T-cell AP-1 CD45RO Tax 潜伏感染 CD45 IL-2

项目摘要

1) Human T cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) are retroviruses with similar biological properties. HTLV-1 is the causative agent of an aggressive T cell leukemia, whereas HTLV-2 has only been associated with a few cases of lymphoproliferative disorders. We show that HTLV-2 Tax2 transformed a Rat-1 fibroblast cell line to form colonies in soft agar, but the size and number of the colonies were less than those of HTLV-1 Tax1. Chimefic Tax protein showed that the C-terminal 300-353 amino acid was responsible for the high transforming activity of Tax1. Our results showed that Tax2 has a lower transforming activity than Tax1, and suggest that the high transforming activity of Tax1 is involved in the leukemogenic property of HTLV-1.2) HTLV-1 is exclusively detected in CD45RO+ T-cells in infected individuals, but CD45RO is weakly expressed in HTLV-1-transformed T-cell lines in vitro. Flow-cytometry showed that only two out of eight interleukin(IL)-2-independent HTLV 1-transformed T-cell lines expressed CD45RO, whereas all five IL-2-dependent ones expressed CD45RO, and the level of expression was higher in IL-2-dependent than in IL-2-independent cells. Using western blotting, we showed that IL-2-dependent HTLV-1-transformed T-cell lines expressed a lower level of expression of Tax1 than IL-2-independent ones, and that the level of expression correlated inversely with that of CD45RO. Our results suggest that CD45RO+ Tax-low IL-2-dependent T-cell lines in vitro correspond to the persistent HTLV-1-infected cells in vivo, and HTLV-1-infected cells in vivo are immortalized in IL-2-dependent manner.3) Tax induced the expression of cyclin D1, D2 and bcl-xl in T-cell lines. Moreover, the induction of these genes was well correlated with the IL-2-independent growth of mouse T-cell lines. These results suggest that Tax-indcued expression of cyclin D1, D2 and bcl-xl play roles in the inhibition of the apoptosis and cell cycle promotion in HTLV-1-infected T-cells.

1）人类T细胞白血病病毒1型（HTLV-1）和2型（HTLV-2）是具有相似生物学特性的逆转录病毒。 HTLV-1是攻击性T细胞白血病的致病药物，而HTLV-2仅与几例淋巴增生性疾病有关。我们表明，HTLV-2税收2将大鼠-1成纤维细胞系转化为软琼脂中的菌落，但菌落的大小和数量小于HTLV-1税务1的菌落。 Chimefic税收蛋白表明，C末端300-353氨基酸负责税务1的高转化活性。我们的结果表明，税收2的转型活动比税务1低，这表明税务1的高转化活动参与了HTLV-1.2）HTLV-1的白血病特性，在受感染个体中CD45RO+ T细胞中仅检测到HTLV-1的性能，但CD45RO在HTLV-1-1-1-Transform-Transform transformed T-transform t-transformed t-c-transformed t-c-ell-t-c-ell t c-elly totro中均未表达。流程度仪表明，八个白介素（IL）-2独立于htlv 1转化的T型T细胞线均表达CD45RO，而所有五个IL-2依赖性CD45RO表达CD45RO，并且在IL-2依赖性IL-2依赖性细胞中表达CD45RO，而IL-2依赖性的表达水平均高。使用蛋白质印迹，我们表明IL-2依赖性HTLV-1转化的T细胞线表达了比IL-2非依赖性的税收1的表达水平较低，并且表达水平与CD45RO的表达水平相关。我们的结果表明，在体外，CD45RO+税收-2依赖性T细胞系在体内对应于持续的HTLV-1感染细胞，而体内的HTLV-1感染的细胞则以IL-2依赖性方式永生化。此外，这些基因的诱导与小鼠T细胞系的IL-2非依赖性生长良好相关。这些结果表明，Cyclin D1，D2和Bcl-XL的税收指标在抑制HTLV-1感染的T细胞中的细胞凋亡和细胞周期促进中起着作用。