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

Tax 和 HBZ 在 HTLV-1C 体内复制中的作用

• 批准号: 10673788
• 负责人: CHRISTOPHE P NICOT
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10673788
• 关键词: Adult; Amino Acid Sequence; Applications Grants; Area; Attention; Australia; Biology; Cells; Data; Disease; Event; Functional disorder; Future; Genetic; Goals; HTLV-1 Infection; Health; High Prevalence; Human T-lymphotropic virus 1; Immune; Immune system; Immunodominant Epitopes; In Vitro; Indigenous; Individual; Infection; Inflammation; Inflammatory; Island; Laboratories; Link; Lung diseases; Melanesian; Modeling; Molecular; Molecular Cloning; Morbidity - disease rate; Mutagens; Mutate; NF-kappa B; Neurodegenerative Disorders; Oryctolagus cuniculus; Pathogenesis; Pathogenicity; Patients; Peptides; Population; Preventive vaccine; Proliferating; Public Health; Publishing; Pulmonary Inflammation; Reporting; Research; Research Proposals; Risk; Role; Sequence Alignment; Sequence Analysis; Sexually Transmitted Diseases; Survival Rate; Taxes; Testing; Time; Variant; Viral; Viral Genes; Viral Proteins; Viral Regulatory Proteins; Virus; Virus Replication; chronic infection; curative treatments; epidemiology study; experimental study; genetic regulatory protein; immune clearance; in vivo; infection rate; innovation; leukemia; mutant; new therapeutic target; novel; prevent; response; tax Gene Products; tax Genes; therapeutic development; therapeutically effective

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.

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。本研究的短期目标是证明病毒基因Tax和HBZ对HTLV-1C的分化复制和体内免疫逃逸至关重要。宿主免疫防御无法有效地清除HTLV-1C Tax和HBZ表达细胞，导致更高的原负荷和炎症。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感染与致命性疾病有关；没有治愈的治疗方法，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在全球传播的风险。这项研究将首次利用兔子模型揭示HTLV-1C感染和体内复制。在澳大利亚中部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。该项目将通过更好地了解HTLV-1C生物学和发病机制，并有助于未来开发预防htlv -1相关疾病的治疗方法，对健康产生积极影响。这个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病毒在体内的感染性和复制性。由于缺乏HTLV-1C分子克隆，这些实验之前都没有做过。序列分析显示，迄今为止发表的所有HTLV-1C序列中，Tax和HBZ免疫显性表位都发生了突变。反过来，我们认为这将阻止宿主对感染细胞的免疫清除，导致更高的前病毒负荷和增加的炎症。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。