T-cell Transformation by Oncoviruses

肿瘤病毒对 T 细胞的转化

• 批准号: 6433047
• 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/6433047
• 关键词: cell cycle; cell transformation; cyclin dependent kinase; cytokine receptors; enzyme activity; genetic mapping; human T cell leukemia; human T cell lymphotropic virus type 1; human T cell lymphotropic virus type 2; human tissue; interleukin 2; nucleic acid sequence; protein sequence; receptor binding; receptor expression; transforming virus; viral carcinogenesis; virulence; virus genetics; virus protein

We are interested in the mechanism of HTLV-I induced T-cell proliferation and the main thrust of our work is to use HTLV-I in vitro to understand the viral and cellular factors involved 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 b and gc chains. We have found that this interaction results in an increase of STAT5 activation 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 b 2 microglobulin. Biochemical studies are in progress to understand the alteration in maturation and trafficking of MHC I in the presence of p12I. Very recently we have identified the function of another HTLV-I small protein, p30II. This protein interferes with several of p53's functions and together with Tax may help the virus to circumvent checkpoints of cell growth. During this year, we also discovered a new virus in a pig-tailed macaque with Sezary syndrome. This virus, like the human EBV, phylogenetically belongs to the lymphocryptoviruses. This virus (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, thus providing a small-animal model for lymphoma whereby to assess therapeutic approaches.

我们对HTLV-I诱导T细胞增殖的机制很感兴趣，我们工作的主要目的是利用HTLV-I在体外了解参与T细胞转化的病毒和细胞因子。 在HTLV-1的情况下，我们集中在12 kD的病毒蛋白（p12 I），这是一个小的致癌基因，并结合到IL-2 R B和gc链。 我们已经发现这种相互作用导致STAT 5激活的增加，并假设这种作用在体内可能是重要的。 此外，我们已经证明p12 I存在于自然界中的两个等位基因中（在患者样本中发现）：一个在位置88携带赖氨酸，并且是泛素化的，具有半小时的半衰期，而另一个天然等位基因在位置88携带精氨酸，并且非常稳定。p12 I也被HTLV-1感染细胞血清中的抗体识别。一项新的发现是p12 I与游离的MHC I重链结合，并干扰其与B 2微球蛋白的结合。生物化学研究正在进行中，以了解在p12 I存在下MHC I成熟和运输的改变。 最近，我们已经确定了另一种HTLV-I小蛋白p30 II的功能。 这种蛋白质干扰p53的几种功能，并与Tax一起可能有助于病毒绕过细胞生长的检查点。 在这一年里，我们还在一只患有塞扎里综合征的猪尾猕猴身上发现了一种新病毒。 这种病毒，像人类EBV一样，在遗传学上属于淋巴隐病毒。 该病毒（HVMNE）分离自淋巴瘤CD 8 + T细胞系，该细胞系由该患病动物的血液和皮肤产生。在兔中接种后，HVMNE以高频率引起淋巴瘤，从而提供淋巴瘤的小动物模型，由此评估治疗方法。