T-cell Transformation by Oncoviruses
肿瘤病毒对 T 细胞的转化
基本信息
- 批准号:7592543
- 负责人:
- 金额:$ 138.63万
- 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:AffectBindingBiochemicalCalciumCell LineCell NucleusCellsClonal ExpansionCytotoxic T-LymphocytesDevelopmentGeneticGenetic TranscriptionHumanHuman T-Cell Leukemia VirusesHuman T-lymphotropic virus 2ImmuneImmunosuppressionInfectionLaboratoriesLesionLigationMHC Class I GenesMalignant NeoplasmsMembrane MicrodomainsMessenger RNAMolecularNF-ATOncornavirusesOpen Reading FramesPLC gamma1PathogenesisPhosphorylationPlayProteinsRNA SplicingReceptor SignalingRecruitment ActivityResearchRetroviridaeRoleT-Cell ActivationT-Cell ReceptorT-Cell TransformationT-LymphocyteTaxesTherapeutic immunosuppressionViralViral GenesViral GenomeVirushuman diseaseimmunological synapseleukemianovelnuclear factors of activated T-cellsprevent
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. 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.
我实验室的一个研究方向是了解人类T细胞 白血病/淋巴瘤病毒1型(HTLV-1)发病机制。HTLV-1是唯一已知的逆转录病毒, 会导致人类癌症流行病学、分子和生化证据表明,HTLV-1 在宿主中的持久性与T细胞克隆扩增和随后的积累有关 基因损伤导致白血病因此,了解病毒的机制 坚持是预防白血病发生的关键。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, PLC-γ 1、Vav和用于活化T细胞(LAT)的接头。因此,钙的释放和 活化T细胞核因子(NFAT)转录降低。p12 I和LAT一样, 位于脂筏中,并在几分钟内被招募到免疫突触, TCR连接。p12 I还通过抑制细胞增殖, 细胞毒性T细胞这些结果可能与免疫抑制和免疫逃避有关 在HTLV-1感染中观察到。另一个令人兴奋的新进展是, 病毒基因组3端ORF II编码的p30 II蛋白减少 通过一种新的转录后机制表达前病毒。我们发现p30 II与 双剪接的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也通过降低p30 II的水平来降低病毒复制。 税。在HTLV-2中也发现了一种具有类似功能的蛋白质(p28 II),HTLV-2是一种遗传上 与HTLV-1有关。我实验室的一项研究与了解人类T细胞有关 细胞白血病/淋巴瘤病毒1型(HTLV-1)发病机制。HTLV-1是唯一已知的逆转录病毒 会导致人类癌症流行病学、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免疫应答相关。 遗传病变的积累,导致白血病。因此,对机制的理解 病毒持续存在对预防白血病的发生至关重要。我们继续研究 由病毒的3端编码的p12 I和p30 II蛋白的功能 基因组我们假设它们可能在病毒持续存在中起重要作用, 发病机制我们发现p12 I影响近端T细胞受体(TCR)信号传导, PLC-γ 1、Vav和接头的磷酸化,用于活化T细胞(LAT)。因此,委员会认为, 钙释放和活化T细胞核因子(NFAT)转录减少。 p12 I与LAT一样,位于脂筏中,并被募集到免疫突触 在TCR连接的几分钟内。p12 I还降低了MHC I类限制性识别, 细胞毒性T细胞的靶向细胞。这些发现可能与免疫抑制有关, 在HTLV-1感染中观察到免疫逃避。另一个令人兴奋的新发展是 发现由病毒3端ORF II编码的p30 II蛋白, 基因组通过一种新的转录后机制降低前病毒的表达。我们发现 p30 II与双剪接的Tax/雷克斯mRNA结合并将其保留在细胞核中。正如所预料的那样, 在HTLV-1感染的T细胞系中,p30 II的表达也通过以下方式降低病毒复制: 降低税收水平。在HTLV-2中也发现了具有类似功能的蛋白质(p28 II), 一种与HTLV-1基因相关的病毒
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Genoveffa Franchini其他文献
Genoveffa Franchini的其他文献
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