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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是侵袭性T细胞白血病的病原体，而HTLV-2仅与少数淋巴组织增生性疾病相关。我们表明，HTLV-2 Tax 2转化大鼠-1成纤维细胞系在软琼脂中形成集落，但集落的大小和数量小于HTLV-1 Tax 1。Tax蛋白的C端300-353位氨基酸是Tax 1具有高转化活性的原因。结果表明，Tax 2的转化活性低于Tax 1，提示Tax 1的高转化活性与HTLV-1的致白血病性有关。2）HTLV-1只在感染者的CD 45 RO + T细胞中表达，而CD 45 RO在HTLV-1转化的T细胞系中表达较弱。流式细胞术显示，只有两个8白细胞介素（IL）-2非依赖性HTLV 1转化的T细胞系表达CD 45 RO，而所有5个IL-2依赖性的表达CD 45 RO，和表达水平高于IL-2依赖性细胞比IL-2非依赖性细胞。使用蛋白质印迹法，我们发现，IL-2依赖性HTLV-1转化的T细胞系表达较低水平的Tax 1比IL-2非依赖性的表达，表达水平与CD 45 RO呈负相关。结果表明，体外培养的CD 45 RO + Tax低IL-2依赖性T细胞系与体内持续性HTLV-1感染的细胞相对应，HTLV-1感染的细胞在体内以IL-2依赖的方式永生化。此外，这些基因的诱导与小鼠T细胞系的IL-2非依赖性生长密切相关。这些结果表明Tax诱导的cyclin D1、D2和bcl-xl的表达在抑制HTLV-1感染的T细胞的凋亡和促进细胞周期中起作用。