T-cell Transformation by Oncoviruses

肿瘤病毒对 T 细胞的转化

• 批准号: 6761578
• 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/6761578
• 关键词: Epstein Barr virus; MHC class I antigen; Macaca; cell cycle; cell transformation; cytokine receptors; genetic mapping; human T cell leukemia; human T cell lymphotropic virus type 1; human T cell lymphotropic virus type 2; interleukin 2; nucleic acid sequence; protein binding; protein sequence; protein structure function; receptor binding; receptor expression; transforming virus; viral carcinogenesis; virulence; 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-I, we have focused on a viral protein (p12I) of 12 kD, which is a small oncogene and binds to the IL-2R beta and gamma-c chains. We have found that this interaction results in an increase of STAT5 activation (Nicot et al., Blood, 2001) and hypothesized that this effect may be important in vivo. In addition, we have demonstrated that p12I exists in two alleles in nature (found in patient samples): one carries in position 88 a Lysine and is ubiquitinated and has a half-life of a half of an hour whereas the other natural allele carries an Arginine in position 88 and is very stable. p12I also is recognized by antibodies in sera of HTLV-I infected cells. A new finding is that 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 studies are in progress to understand the alteration in maturation and trafficking of MHC I in the presence of p12I and the mechanism of STAT5 activation. In addition, very recently we have identified the function of another HTLV-I small protein, p30II. This protein interferes with p53's function and together with Tax may help the virus to circumvent checkpoints of cell growth. We have discovered that p30II is a negative regulator of viral expression and in concert with p12I may allow expansion of infected cells. Thus, efforts to target p30II may prove worthwhile for possible therapeutic intervention. During this year, we also discovered a new virus (HVMNE) in 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 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.

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。在HTLV-I的情况下，我们关注的是12kd的病毒蛋白（p12I），这是一个小的致癌基因，与IL-2R β和γ -c链结合。我们发现这种相互作用导致STAT5激活增加（Nicot et al., Blood, 2001），并假设这种作用在体内可能很重要。此外，我们已经证明p12I存在于自然界的两个等位基因中（在患者样本中发现）：一个在88号位置携带赖氨酸，被泛素化，半衰期为半小时，而另一个天然等位基因在88号位置携带精氨酸，非常稳定。HTLV-I感染细胞血清中的抗体也能识别p12I。一项新的发现是p12I结合到游离MHC I重链上，并干扰其与β -2微球蛋白的关联(Johnson等人，J. Virol。, 2001)。生化研究正在进行中，以了解p12I存在时MHC I的成熟和运输的变化以及STAT5激活的机制。