T-cell Transformation by Oncoviruses

我们工作的主旨是使用人类病毒转化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，分别由病毒基因组的ORFI和II编码。P12I是一种小的癌基因，它与IL-2Rβ和伽马-c链以及MHC I等受体结合，促进STAT5的激活(Nicot等人，布拉德，2001)和细胞增殖。然而，最近我们发现p12I存在于RAFT中并下调TCR近端信号通路，目前我们正在寻找p12I的细胞伙伴来实现这一作用。P12I与游离的MHC I重链结合并干扰其与β-2微球蛋白的结合(Johnson等人，J.Virol，2001)。生化和生物学研究表明，在p12I存在的情况下，MHC I的成熟和转运发生改变，导致抗原提呈减少，CTL识别能力下降。我们最近发现了p30II的功能，它是一种病毒表达的负调控因子，专门针对mRNA。这种蛋白是病毒表达的正向调节因子。因此，p30II对于抑制体内至少部分病毒复制可能是非常重要的(潜伏？)并允许逃避对HTLV-1感染细胞的免疫监视(Nicot等人，提交，2003年)。P30II可能被证明是一个值得进行治疗干预的靶点。我们继续对从患有Sezary综合征的猪尾猕猴中分离出的一种新病毒(HVMNE)进行研究。这种病毒和人类EBV一样，在系统发育上属于淋巴病毒。HVMNE是从淋巴瘤CD8+T细胞系中分离出来的，该细胞系从这种疾病动物的血液和皮肤中产生。在兔体内接种后，HVMNE会导致高频率的T细胞淋巴瘤(Ferrari等人，布拉德，2001)，从而提供了一种淋巴瘤的小动物模型，借此评估治疗方法和T细胞转化所涉及的遗传决定因素，这可能有助于人类淋巴瘤的治疗。最近，我们已经证明了病毒在体外也会导致非人类灵长类动物的T细胞转化(Ferrari等人，病毒学，在出版社)。

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).