T-cell Transformation by Oncoviruses
肿瘤病毒对 T 细胞的转化
基本信息
- 批准号:7337917
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
One line of research in my laboratory is related to understanding human T cell leukemia/lymphoma virus type 1 (HTLV-1) pathogenesis. HTLV-1 is the only known retrovirus that causes human cancer. Epidemiological, molecular, and biochemical evidence suggests that HTLV-1 persistence in the host is associated with T cell clonal expansion and consequent accumulation of genetic lesions, resulting in leukemia. Thus, the understanding of mechanisms of viral persistence is essential to prevent the occurrence of leukemia. We continued to study the function of the p12I and p30II proteins encoded by the 3' end of the viral genome. We hypothesized that they may play an essential role in viral persistence and pathogenesis. We found that p12I affects proximal T cell receptor (TCR) signaling, and phosphorylation of PLC-gamma1, Vav, and linker for activation of T cells (LAT). Consequently, calcium release and nuclear factor of activated T cells (NFAT) transcription are decreased. p12I, like LAT, is located in the lipid rafts and is recruited to the immunological synapse within minutes from TCR ligation. p12I also decreased MHC class I-restricted recognition of targeted cells by cytotoxic T cells. These findings may relate to the immunosuppression and immune evasion observed in HTLV-1 infection. Another exciting new development has been the finding that the p30II protein encoded by the ORF II at the 3' end of the viral genome decreases proviral expression by a novel post-transcriptional mechanism. We found that p30II binds to the doubly spliced Tax/Rex mRNA and retains it in the nucleus. As expected, expression of p30II in HTLV-1-infected T cell lines also decreases viral replication by decreasing the level of Tax. A protein (p28II) with similar function is also found in HTLV-2, a virus genetically related to HTLV-1.
我实验室的一项研究与了解人类T细胞白血病/淋巴瘤病毒1型(HTLV-1)的发病机制有关。HTLV-1是唯一已知的导致人类癌症的逆转录病毒。流行病学、分子和生物化学证据表明,HTLV-1在宿主中的持续存在与T细胞克隆扩增和随后的遗传病变积累相关,导致白血病。因此,了解病毒持续存在的机制对于预防白血病的发生至关重要。我们继续研究由病毒基因组3'端编码的p12 I和p30 II蛋白的功能。我们推测它们可能在病毒的持续存在和发病机制中起重要作用。我们发现p12 I影响近端T细胞受体(TCR)信号传导,以及PLC-γ 1、Vav和用于活化T细胞(LAT)的连接子的磷酸化。因此,钙释放和活化T细胞核因子(NFAT)转录减少。p12 I,像LAT一样,位于脂筏中,并在TCR连接后几分钟内被募集到免疫突触。p12 I还降低了细胞毒性T细胞对靶细胞的MHC I类限制性识别。这些发现可能与HTLV-1感染中观察到的免疫抑制和免疫逃避有关。另一个令人兴奋的新进展是发现由病毒基因组3'端的ORF II编码的p30 II蛋白通过一种新的转录后机制降低前病毒表达。我们发现,p30 II结合到双重剪接的Tax/雷克斯mRNA,并将其保留在细胞核中。正如预期的那样,在HTLV-1感染的T细胞系中p30 II的表达也通过降低Tax的水平来降低病毒复制。在HTLV-2中也发现了具有类似功能的蛋白质(p28 II),HTLV-2是一种与HTLV-1遗传相关的病毒。
项目成果
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Genoveffa Franchini其他文献
Genoveffa Franchini的其他文献
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INDUCTION OF SIV-SPECIFIC CD8+ INTRAEPITHELIAL LYMPHOCYTES
SIV 特异性 CD8 上皮内淋巴细胞的诱导
- 批准号:
6939813 - 财政年份:2003
- 资助金额:
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6939800 - 财政年份:2003
- 资助金额:
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2463673 - 财政年份:
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7038625 - 财政年份:
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- 批准号:
6761611 - 财政年份:
- 资助金额:
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Role of the HTLV-1A and HTLV1-C inflammatory profile in disease
HTLV-1A 和 HTLV1-C 炎症谱在疾病中的作用
- 批准号:
10014283 - 财政年份:
- 资助金额:
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