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，以开发更有效的治疗疗法。该提案的短期目标是证明病毒基因税和HBZ对于在体内发散的HTLV-1C复制和免疫逃生至关重要。宿主免疫防御能力有效消除HTLV-1C税和表达细胞的HBZ导致较高的病毒载荷和炎症。该项目将研究与炎症和肺部疾病有关的病毒事件。该研究提案很重要，因为HTLV-1的感染与致命疾病有关。没有治疗性治疗，几乎没有治疗选择和总体4年生存率的差。此外，诸如HTLV-1之类的性传播疾病可以扩散到孤立的种群之外，并增加全球HTLV-1C传播的风险。进行的研究将首次使用兔子模型在体内对HTLV-1C感染和复制进行启示。居住在偏远地区的土著成年人中，澳大利亚中部的HTLV-1C感染超过40％，其中多达30％的人患有归因于HTLV-1感染的疾病。该项目将通过更好地了解HTLV-1C生物学和发病机理，并有助于预防HTLV-1相关疾病的未来发展，从而产生积极的健康影响。该项目具有创新性，因为它将使用我的实验室中开发的第一个也是唯一的HTLV-1C传染性分子克隆来研究体内HTLV-1C病毒感染和复制。由于缺乏HTLV-1C分子克隆，这些实验均未进行。序列分析表明，迄今为止所有发布的HTLV-1C序列中都均在所有HTLV-1C序列中突变税和HBZ免疫主导表位。反过来，我们认为这将防止宿主对感染细胞的免疫清除，导致前病毒负荷和炎症增加。了解所涉及的分子机制可能会为治疗HTLV-1疾病的治疗提供新的治疗靶点。