T-cell Transformation by Oncoviruses

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-I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 β和γ-c链。我们已经发现，这种相互作用导致STAT 5活化的增加（Nicot等人，Blood，2001），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。一个新的发现是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年）。生物化学研究正在进行中，以了解在p12 I存在下MHC I成熟和运输的改变以及STAT 5激活的机制。 此外，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的功能，并与Tax一起帮助病毒绕过细胞生长的检查点。我们已经发现p30 II是病毒表达的负调节因子，并且与p12 I一致可以允许受感染细胞的扩增。因此，靶向p30 II的努力可能证明值得进行可能的治疗干预。 在这一年中，我们还在一只患有Sezary综合征的猪尾猕猴中发现了一种新病毒（HVMNE）。这种病毒，像人类EBV一样，在遗传学上属于淋巴隐病毒。HVMNE分离自淋巴瘤性CD 8 + T细胞系，其产生自该患病动物的血液和皮肤。在兔中接种后，HVMNE以高频率引起淋巴瘤（Ferrari等人，Blood，2001），从而提供了淋巴瘤的小动物模型，从而评估可能有助于治疗人淋巴瘤的治疗方法和涉及T细胞转化的遗传决定因素。

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.