T-cell Transformation by Oncoviruses

肿瘤病毒对 T 细胞的转化

• 批准号: 7038611
• 负责人: Genoveffa Franchini
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7038611
• 关键词: MHC class I antigen; Macaca; T cell receptor; antigen presentation; cell proliferation; cell transformation; cytokine receptors; gene expression; human T cell leukemia; human T cell lymphotropic virus type 1; interleukin 2; oncogenes; protein binding; protein structure function; protein transport; receptor binding; receptor expression; viral carcinogenesis; virus genetics; virus protein

The main thrust of our work is to use in vitro models of transformation of T cells by human viruses to understand the role of viral and cellular proteins in T cell transformation. In the case of HTLV-1, we have focused on two viral proteins, p12I and p30II, encoded by the ORFs I and II of the viral genome, respectively. p12I is a small oncogene that binds to receptors such as the IL2R beta and gamma-c chains and the MHC I. p12I increases Stat5 activation (Nicot et al., Blood 2001) and cell proliferation. Recently, however, we found that p12I is in the raft and downregulates the TCR proximal signaling pathway and is recruited to the immunological synapse. We are working on the identification of the cellular partner of p12I for this effect. p12I binds to the free MHC I heavy chain and interferes with its association with the beta-2 microglobulin (Johnson et al., J Virol 2001). Biochemical and biological data indicate that the alteration in maturation and trafficking of MHC I in the presence of p12I results in decreased antigen presentation and decreased CTL recognition. We recently uncovered the function of p30II, a negative regulator of viral expression that specifically targets the mRNA. This protein is a negative regulator of viral expression and may be very important for virus concealment in vivo (latency) and allow escape from immune recognition (Nicot et al., Nat Med 2004). p30II indeed may be a desirable target for therapeutic intervention. References: Harrod et al. J Biol Chem 2003; Johnson et al. in Sugamura K et al.: Two Decades of Adult T-Cell Leukemia and HTLV-1 Research. 2003; Franchini et al Int J Hematol 2003; Younis et al. J Virol. 2004.

我们工作的主要目的是使用体外模型的T细胞转化的人类病毒，以了解病毒和细胞蛋白在T细胞转化中的作用。在HTLV-1的情况下，我们集中在两个病毒蛋白，p12 I和p30 II，分别由病毒基因组的ORF I和II编码。p12 I是一种小的致癌基因，其与受体如IL 2 R β和γ-c链以及MHC I结合。p12 I增加Stat 5活化（Nicot等人，Blood 2001）和细胞增殖。然而，最近，我们发现，p12 I是在筏和下调TCR近端信号通路，并招募到免疫突触。我们正在鉴定p12 I的细胞伴侣以实现这种效果。p12 I与游离的MHC I重链结合并干扰其与β-2微球蛋白的结合（约翰逊等人，J Virol 2001）。生化和生物学数据表明，在p12 I的存在下，MHC I的成熟和运输的改变导致抗原呈递减少和CTL识别减少。我们最近发现了p30 II的功能，p30 II是一种特异性靶向mRNA的病毒表达负调节因子。该蛋白质是病毒表达的负调节剂，并且对于体内病毒隐藏（潜伏期）可能非常重要，并且允许逃避免疫识别（Nicot et al.，Nat Med 2004）。p30 II确实可能是治疗干预的理想靶点。参考文献：Harrod等人，J Biol Chem 2003;约翰逊等人，Sugamura K等人：成人T细胞白血病和HTLV-1研究的二十年。2003; Franchini等Int J Hematol 2003; Younis等J Virol. 2004.