T-cell Transformation by Oncoviruses

肿瘤病毒对 T 细胞的转化

• 批准号: 6950120
• 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/6950120
• 关键词: Gammaherpesvirinae; MHC class I antigen; T cell receptor; T lymphocyte; biological signal transduction; human T cell lymphotropic virus type 1; neoplastic transformation; oncogenes; protein structure function; receptor expression; tissue /cell culture; viral carcinogenesis; virus protein; virus related neoplasm /cancer

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 IL-2R beta and gamma-c chains and the MHC I. p12I increases STAT5 activation (Nicot et al., Blood, 2001) and cell proliferation. Recently, however, we have found that p12I is in the raft and downregulates the TCR proximal signaling pathway, and we are at present 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 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 have recently uncovered the function of p30II, a negative regulator of viral expression that specifically targets the mRNA. This protein is a positive regulator of viral expression. Thus, p30II may be very important to suppress at least partially viral replication in vivo (latency?) and allow escape from immune surveillance of HTLV-1-infected cells (Nicot et al., submitted, 2003). p30II may prove to be a worthwhile target for therapeutic intervention. We have continued our research on a new virus (HVMNE) isolated from a pig-tailed macaque with Sezary syndrome. This virus, like the human EBV, phylogenetically belongs to the lymphocryptoviruses. HVMNE was isolated from lymphomatous CD8+ T-cell lines, generated from the blood and skin of this diseased animal. Upon inoculation in rabbits, HVMNE causes T-cell lymphomas with high frequency (Ferrari et al., Blood, 2001), thus providing a small-animal model for lymphoma whereby to assess therapeutic approaches and the genetic determinants involved in T-cell transformation that may help in the treatment of human lymphoma. More recently, we have demonstrated that the virus causes transformation of T-cells in nonhuman primates in vitro as well (Ferrari et al., Virology, in press).

我们工作的主要目的是利用人类病毒转化t细胞的体外模型来了解病毒和细胞蛋白在t细胞转化中的作用。以HTLV-1为例，我们重点研究了两种病毒蛋白p12I和p30II，它们分别由病毒基因组的orf I和orf II编码。p12I是一种小的致癌基因，与IL-2R β和γ -c链以及MHC i等受体结合。p12I增加STAT5的激活（Nicot等人，Blood, 2001）和细胞增殖。然而，最近，我们发现p12I在筏中并下调TCR近端信号通路，我们目前正在研究p12I的细胞伴侣以达到这种效果。p12I结合到游离的MHC I重链上，并干扰其与β -2微球蛋白的结合(Johnson等，J. Virol。, 2001)。生化和生物学表明，在p12I存在下，MHC I成熟和运输的改变导致抗原呈递减少和CTL识别降低。我们最近发现了p30II的功能，p30II是一种专门针对mRNA的病毒表达的负调节因子。这种蛋白是病毒表达的正向调节因子。因此，p30II可能对至少部分抑制病毒在体内的复制（潜伏期？）并使其逃脱htlc -1感染细胞的免疫监视非常重要（Nicot等人，提交，2003）。p30II可能被证明是一个有价值的治疗干预目标。我们继续对从患有塞扎里综合征的长尾猕猴身上分离出的一种新病毒（HVMNE）进行研究。这种病毒和人类eb病毒一样，在系统发育上属于淋巴隐病毒。HVMNE是从该患病动物的血液和皮肤产生的淋巴瘤CD8+ t细胞系中分离出来的。在家兔中接种后，HVMNE高频率地引起t细胞淋巴瘤（Ferrari et al., Blood, 2001），从而为淋巴瘤提供了一个小动物模型，用于评估治疗方法和参与t细胞转化的遗传决定因素，这可能有助于治疗人类淋巴瘤。最近，我们已经证明该病毒在体外也能引起非人灵长类动物t细胞的转化（Ferrari等人，病毒学，出版中）。