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 仅与少数淋巴细胞增殖性疾病病例相关。我们发现，HTLV-2 Tax2 转化了 Rat-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均小于 HTLV-1 Tax1。 Chimefic Tax蛋白显示C端300-353个氨基酸负责Tax1的高转化活性。我们的结果表明，Tax2 的转化活性低于 Tax1，表明 Tax1 的高转化活性与 HTLV-1.2 的致白血病特性有关。HTLV-1 只在感染个体的 CD45RO+ T 细胞中检测到，但 CD45RO在体外 HTLV-1 转化的 T 细胞系中微弱表达。流式细胞术显示，8个不依赖白细胞介素(IL)-2的HTLV 1转化T细胞系中只有2个表达CD45RO，而所有5个IL-2依赖的T细胞系都表达CD45RO，并且在IL中表达水平较高-2 依赖性细胞多于非 IL-2 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T细胞系表达的Tax1表达水平低于IL-2非依赖性T细胞系，并且表达水平与CD45RO呈负相关。我们的结果表明，体外 CD45RO+ Tax-low IL-2 依赖性 T 细胞系对应于体内持续 HTLV-1 感染的细胞，并且体内 HTLV-1 感染的细胞以 IL-2 依赖性方式永生化.3) Tax诱导T细胞系中细胞周期蛋白D1、D2和bcl-xl的表达。此外，这些基因的诱导与小鼠 T 细胞系的不依赖 IL-2 的生长密切相关。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发挥作用。