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-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，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，我们目前正在鉴定的细胞伴侣的p12 I的这种效果。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年）。生物化学和生物学研究表明，p12 I的存在改变了MHC I的成熟和运输，导致抗原提呈减少和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。这种蛋白质是病毒表达的正调控因子。因此，p30 II可能是非常重要的，以抑制至少部分病毒复制在体内（潜伏期？）并允许从HTLV-1感染细胞的免疫监视中逃逸（Nicot等，2003年提交）。p30 II可能被证明是一个值得治疗干预的目标。我们继续对一种新病毒（HVMNE）进行研究，该病毒分离自患有Sezary综合征的猪尾猕猴。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T细胞淋巴瘤（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。最近，我们已经证明该病毒也在体外引起非人灵长类动物中的T细胞转化（Ferrari等人，Virology，in press）.

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).