Disruption of Antiviral Signaling Pathways by HTLV-I Tax

人T细胞白血病病毒I型（HTLV-1）是一种致癌逆转录病毒，与T细胞白血病的发生有关。 成人T细胞白血病-淋巴瘤（ATLL）和称为HTLV-1相关的神经炎性疾病 脊髓病/热带痉挛性轻瘫（HAM/TSP）。疾病发生和进展的决定因素 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的适应性免疫应答和随后的免疫逃避策略已经被证实是有效的。 详细研究，很少有人知道HTLV-1使用的机制，以抵消先天臂的 免疫反应I型干扰素（IFN-α/β）对于限制病毒复制和建立有效的抗病毒治疗是至关重要的。 抗病毒状态I型干扰素的表达受到严格的调控，并受到病毒感染的强烈诱导 这是由于Toll依赖性和非依赖性先天性抗病毒信号通路的激活。收费- 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Barber博士一起，我们发现Tax是Toll依赖性和 独立的先天抗病毒途径。税收抑制这些途径的一部分是通过与里皮相互作用， Barber博士的实验室最近确定了RIG-I的重要组成部分， 介导的信号传导。除了干扰素产生的调节途径外， 发现Tax通过STATI磷酸化下游的独特核机制抑制IFN信号传导 和DNA结合与这些发现相关的是，我们还发现Tax与STATI和SOCS 1相互作用， IFN信号的重要调节剂。因此，Tax是一种独特的病毒癌蛋白， 先天性抗病毒信号传导途径抑制IFN的产生和信号传导。我们建议进一步界定 税收抑制这些重要信号通路的机制。我们将采取以下具体措施 目的：（1）HTLV-1 Tax对先天性信号传导的调控;（2）HTLV-1 Tax介导的细胞内信号传导机制 IFN信号传导的抑制。完成拟议的研究将提供机制的见解， Tax破坏抗病毒信号通路，可能导致HTLV-1相关的新疗法 疾病 相关性（参见说明）： HTLV-1是成人T细胞白血病-淋巴瘤（ATLL）的病原体，ATLL是一种侵袭性恶性肿瘤， CD 4 + T淋巴细胞。尽管对HTLV-1的适应性免疫应答已经被广泛研究， 关于HTLV-1和先天性抗病毒免疫，特别是I型干扰素之间的相互作用是已知的 (IFN)相关路径该提案的重点是确定HTLV-I使用的机制， 编码Tax癌蛋白拮抗RIG-1/MDA-5抗病毒途径和IFN信号传导。

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.