Disruption of Antiviral Signaling Pathways by HTLV-I Tax

人T细胞白血病病毒I型(HTLV-1)是一种与人T细胞白血病病毒I型(HTLV-1)相关的致癌逆转录病毒。 成人T细胞白血病-淋巴瘤(ATLL)和一种名为HTLV-1的神经炎性疾病 脊髓病/热带痉挛截瘫(HAM/TSP)。疾病发生和发展的决定因素 在很大程度上是未知的，但宿主免疫反应的有效性似乎发挥了重要作用。 尽管对HTLV-1的获得性免疫反应和随后的免疫逃避策略 经过详细研究，人们对HTLV-1用来中和人的先天手臂的机制知之甚少 免疫反应。I型干扰素(干扰素-o/p)对于限制病毒复制和建立有效的 抗病毒状态。I型IFN的表达受到严格的调控，并受到病毒感染的强烈诱导 由于Toll依赖和独立的先天抗病毒信号通路的激活。通行费- 独立的途径利用RNA解旋酶RIG-I和MDA-5来检测细胞质中的病毒RNA。 与巴伯博士一起，我们发现税收是一种有效的抑制通行费依赖和 独立的先天抗病毒途径。税收在一定程度上通过与死亡的Ripi相互作用来抑制这些途径 含有蛋白质的结构域，巴伯博士的实验室最近发现这种蛋白质是RIG-I的基本成分- 中介信号。除了它在扰乱调节干扰素产生的途径上的作用外，它还 发现TAX通过STATI磷酸化下游独特的核机制抑制干扰素信号转导 和DNA结合。与这些发现相关的是，我们还发现税收与STATI和S0CS1相互作用， 干扰素信号的重要调节因子。因此，Tax是一种独特的病毒癌蛋白，它可以破坏 先天抗病毒信号通路可抑制干扰素的产生和信号传递。我们建议进一步界定 税收抑制这些重要信号通路的机制。我们将推行以下具体措施 目的：(1)HTLV-1 Tax对先天信号的调节；(2)HTLV-1 Tax介导的机制 抑制干扰素信号转导。拟议研究的完成将使人们从机械上深入了解 税收干扰抗病毒信号通路，可能导致HTLV-1相关的新疗法 疾病。 相关性(请参阅说明)： HTLV-1是成人T细胞白血病-淋巴瘤(ATLL)的病原体，ATLL是一种侵袭性的恶性肿瘤 CD4+T淋巴细胞。尽管对HTLV-1的获得性免疫反应已经进行了广泛的研究，但很少有 已知HTLV-1和先天抗病毒免疫之间的相互作用，特别是I型干扰素 (干扰素)相关通路。该提案的重点是确定HTLV-I使用的机制- 编码Tax癌蛋白以拮抗RIG-L/mda-5抗病毒途径和干扰素信号转导。

The human T cell leukemia virus type I (HTLV-1) is an oncogenic retrovirus associated with the genesis of adult T cell leukemia-lymphoma (ATLL) and a neuroinflammatory disease termed HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The determinants of disease initiation and progression are largely unknown but the effectiveness of the host immune response appears to play a major role. Although the adaptive immune response to HTLV-1 and subsequent immune evasion strategies have been studied in detail, little is known about mechanisms used by HTLV-1 to counteract the innate arm of the immune response. Type I interferon (IFN-o/p) is critical to restrict viral replication and establish a potent antiviral state. The expression of type I IFNs are tightly regulated and are strongly induced by virus infection due to the activation of Toll-dependent and independent innate antiviral signaling pathways. The Toll- independent pathways utilize the RNA helicases RIG-I and MDA-5 to detect viral RNA in the cytoplasm. Together with Dr. Barber, we have found that Tax is a potent inhibitor of both Toll-dependent and independent innate antiviral pathways. Tax inhibits these pathways in part by interacting with RIPI, a death domain containing protein that Dr. Barber's lab has recently identified as an essential component of RIG-I- mediated signaling. In addition to its effects on disrupting pathways that regulate IFN production, it was also found that Tax inhibits IFN signaling by a unique nuclear mechanism downstream of STATI phosphorylation and DNA binding. Relevant to these findings, we also found that Tax interacts with STATI and S0CS1, important regulators of IFN signaling. Therefore, Tax is a unique viral oncoprotein that disrupts multiple innate antiviral signaling pathways to inhibit IFN production and signaling. We propose to further define the mechanisms by which Tax inhibits these important signaling pathways. We will pursue the following specific aims: (1) Regulation of innate signaling by HTLV-1 Tax and (2) mechanisms of HTLV-1 Tax-mediated inhibition of IFN signaling. Completion of the proposed studies will provide mechanistic insight into the disruption of antiviral signaling pathways by Tax and may lead to novel therapeutics for HTLV-1 associated diseases. RELEVANCE (See instructions): HTLV-1 is the etiological agent of adult T cell leukemia-lymphoma (ATLL), an aggressive malignancy of CD4+ T lymphocytes. Although the adaptive immune response to HTLV-1 has been extensively studied, little is known regarding the interplay between HTLV-1 and innate antiviral immunity, specifically type I interferon (IFN) related pathways. The focus of the proposal is to determine the mechanisms used by the HTLV-I- encoded Tax oncoprotein to antagonize the RIG-l/MDA-5 antiviral pathway and IFN signaling.