Role of Tax and HBZ in HTLV-1C replication in vivo

该项目的长期目标是更好地了解HTLV-1的致病性，以开发更有效的治疗方法。本提案的短期目标是证明病毒基因Tax和HBZ对体内不同的HTLV-1C复制和免疫逃逸至关重要。宿主免疫防御不能有效消除HTLV-1C Tax和HBZ表达细胞导致更高的前病毒负荷和炎症。该项目将调查与炎症和肺部疾病相关的病毒事件。这项研究计划意义重大，因为HTLV-1感染与致命性疾病相关;没有治愈性治疗，治疗选择很少，总体4年生存率非常低。此外，像HTLV-1这样的性传播疾病可以传播到孤立的人群之外，并增加HTLV-1C在全球范围内传播的风险。这项研究将首次揭示HTLV-1C感染和复制在体内使用兔模型。在澳大利亚中部，居住在偏远地区的土著成年人中，HTLV-1C感染率超过40%，其中多达30%的人患有HTLV-1感染引起的疾病。该项目将通过提供对HTLV-1C生物学和发病机制的更好理解，并帮助未来开发预防HTLV-1相关疾病的治疗方法，对健康产生积极影响。该项目的创新之处在于，它将使用我实验室开发的第一个也是唯一一个HTLV-1C感染性分子克隆来研究体内HTLV-1C病毒的感染性和复制。由于缺乏HTLV-1C分子克隆，这些实验以前都没有进行过。序列分析表明，Tax和HBZ免疫显性表位在迄今为止发表的所有HTLV-1C序列中都发生了突变。反过来，我们认为这将阻止宿主对感染细胞的免疫清除，导致更高的前病毒负荷和炎症增加。了解所涉及的分子机制可能为HTLV-1疾病的治疗提供新的治疗靶点。

The long-term goals of this project are to better understand the pathogenicity of HTLV-1 in order to develop more effective therapeutic therapies. The short term objectives of this proposal are to demonstrate that the viral genes Tax and HBZ are critical for divergent HTLV-1C replication and immune escape in vivo. The inability of the host immune defenses to efficiently eliminate HTLV-1C Tax and HBZ expressing cells results in higher proviral loads and inflammation. This project will investigate viral events associated with inflammation and lung disease. This research proposal is significant because infection with HTLV-1 is associated with fatal diseases; there are no curative treatments, few treatment options and a very poor overall 4-year survival rate. In addition, sexually transmitted diseases like HTLV-1 can spread beyond isolated populations and increase the risks of HTLV-1C spreading worldwide. The research conducted will for the first time shed light on HTLV-1C infection and replication in vivo using a rabbit model. HTLV-1C infection in central Australia exceeds 40% among indigenous adults living in remote areas, and as much as 30% of these individuals have diseases attributed to HTLV-1 infection. This project will have a positive health impact by providing a better understanding of HTLV-1C biology and pathogenesis and aid in the future development of therapeutics to prevent HTLV-1-associated diseases. This project is innovative in that it will use the first and only HTLV-1C infectious molecular clone developed in my laboratory to study in vivo HTLV-1C virus infectivity and replication. None of these experiments have been done before due to the lack of an HTLV-1C molecular clone. Sequence analyses have revealed that both Tax and HBZ immunodominant epitopes are mutated in all HTLV-1C sequences published to date. In turn, we believe that this will prevent host immune clearance of infected cells leading to a higher proviral load and increased inflammation. Understanding the molecular mechanisms involved may offer new therapeutic targets for the treatment of HTLV-1 diseases.