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，以便开发更有效的治疗方法。这项提议的短期目标是证明病毒基因Tax和HBZ对体内HTLV-1C的不同复制和免疫逃逸至关重要。宿主免疫防御系统不能有效地清除HTLV-1C Tax和HBZ表达细胞，导致较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。这项研究建议意义重大，因为感染HTLV-1与致命疾病有关；没有根治方法，治疗选择很少，总体4年存活率非常低。此外，像HTLV-1这样的性传播疾病可能会传播到与世隔绝的人群之外，并增加HTLV-1C在全球传播的风险。这项研究将首次揭示HTLV-1C感染和体内复制的兔子模型。在澳大利亚中部，居住在偏远地区的土著成年人中HTLV-1C感染超过40%，这些人中多达30%的人患有可归因于HTLV-1感染的疾病。该项目将通过更好地了解HTLV-1C的生物学和发病机制，对健康产生积极的影响，并有助于未来预防HTLV-1相关疾病的治疗方法的发展。本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HTLV-1C病毒的体内传染性和复制。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，在迄今公布的所有HTLV-1C序列中，TAX和HBZ免疫优势表位都发生了突变。反过来，我们认为这将阻止宿主对感染细胞的免疫清除，从而导致更高的前病毒负荷和更多的炎症。了解相关的分子机制可能为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.