Functional analysis of HTLV-I Tax in vivo using a rat model system

使用大鼠模型系统对 HTLV-I Tax 进行体内功能分析

• 批准号: 15590413
• 负责人: OHASHI Takashi
• 金额: $ 2.3万
• 依托单位: HOKKAIDO UNIVERSITY (2004)Tokyo Medical and Dental University (2003)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590413/
• 关键词: HTLV-I; Tax; ATL; siRNA; CTL; animal model; HTLV-1

Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL). Although the viral transactivation factor, Tax, has known to have the apparent transforming ability, the exact function of Tax for ATL development is still not clear. To understand the role of Tax in ATL development, in this study, we introduced short-interfering RNAs (siRNAs) against Tax in a rat HTLV-1 infected T cell line. Our results demonstrated that expression of siRNA targeting Tax successfully downregulated Tax expression. Repression of Tax expression was associated with resistance of the HTLV-1 infected T cells to Tax-specific cytotoxic T lymphocytes killing. This may be due to the direct effect of decreased Tax expression, because the Tax siRNA did not alter the expression of MHC-I, CD80, nor CD86. Furthermore, T cells with Tax down regulation appeared to lose the ability to develop tumors in T cell-deficient nude rats, in which the parental HTLV-1-infected cells induce ATL-like lymphoproliferative disease. These results indicated the importance of Tax both for activating host immune response against the virus and for maintaining the growth ability of infected cells in vivo. Our results provide insights into the mechanisms how the host immune system can survey and inhibit the growth of HTLV-1-infected cells during the long latent period before the onset of ATL.

人类T细胞白血病病毒1型（HTLV-1）导致成人T细胞白血病（ATL）。尽管病毒反式激活因子Tax具有明显的转化能力，但Tax在ATL形成中的确切作用尚不清楚。为了了解Tax在ATL发展中的作用，在这项研究中，我们在大鼠HTLV-1感染的T细胞系中引入了针对Tax的短干扰RNA（siRNA）。我们的结果表明，表达靶向Tax的siRNA成功下调Tax的表达。Tax表达的抑制与HTLV-1感染的T细胞对Tax特异性细胞毒性T淋巴细胞杀伤的抗性相关。这可能是由于Tax表达降低的直接作用，因为Tax siRNA不改变MHC-I、CD 80和CD 86的表达。此外，Tax下调的T细胞似乎失去了在T细胞缺陷的裸鼠中发展肿瘤的能力，其中亲代HTLV-1感染的细胞诱导ATL样淋巴组织增生性疾病。这些结果表明Tax对于激活宿主对病毒的免疫应答和维持感染细胞在体内的生长能力都是重要的。我们的研究结果提供了深入了解宿主免疫系统如何在ATL发病前的长潜伏期内调查和抑制HTLV-1感染细胞生长的机制。

项目成果

Expansion of Human T-Cell Leukemia Virus Type 1 (HTLV-1) Reservoir in Orally Infected Rats : Inverse Correlation with HTLV-1-Specificc Cellular Immune Response.

人类 T 细胞白血病病毒 1 型 (HTLV-1) 病毒库在口腔感染大鼠中的扩增：与 HTLV-1 特异性细胞免疫反应呈负相关。

• 发表时间: 2003
• 期刊: J virol. 77
• 作者: Nomura M.;et al.;Machiko Nishio;Hasegawa A et al.
• 通讯作者: Hasegawa A et al.

Repressiosn of Tax Expression is Associated Both with Resistance of Human T-Cell Leukemia Virus Type-1-Infected T cells to Tax-Specific Cytotoxic T Lymphocytes Killing and with Impaired Tumorigenecity in a Rat Model.

Tax 表达的抑制与人类 T 细胞白血病病毒 1 型感染的 T 细胞对 Tax 特异性细胞毒性 T 淋巴细胞杀伤的抵抗力以及大鼠模型中致瘤性受损有关。

• 发表时间: 2004
• 期刊: Journal of Virology 78
• 作者: Nomura M.;et al.
• 通讯作者: et al.

Harashima N.et al.: "Graft-versus-Tax response in adult T-cell leukemia patients following hematopoietic stem cell transplantation."Cancer Research. 64. 391-399 (2004)

Harashima N.et al.：“造血干细胞移植后成人 T 细胞白血病患者的移植物抗税反应。”癌症研究。

Expression of small hairpin RNA by lentiviral-based vector confers efficient and stable gene-suppression of HIV-1 on human cells including primary non-dividing cells.

通过基于慢病毒的载体表达小发夹 RNA，可以对人类细胞（包括原代非分裂细胞）进行有效且稳定的 HIV-1 基因抑制。

• 发表时间: 2004
• 期刊: Microbes and Infection 6
• 作者: Takamura;S.;Niikura;M.;Li;T.C.;Takeda;N.;Kusagawa;S.;Takebe;Y.;Miyamura;T.;Yasutomi;Y.;保富康宏;Nishitsuji H.et al.
• 通讯作者: Nishitsuji H.et al.

Inducible co-stimulator (ICOS)-mediated suppression of human immunodeficiency virus type 1-replicationn in CD4+ T lymphocytes.

诱导共刺激剂 (ICOS) 介导的对 CD4 T 淋巴细胞中人类免疫缺陷病毒 1 型复制的抑制。

• 发表时间: 2004
• 期刊: Virology 325
• 作者: Zhou X.;et al.
• 通讯作者: et al.