Role of viral APH-2 in HTLV-2 replication and persistence

病毒 APH-2 在 HTLV-2 复制和持久性中的作用

• 批准号: 8298808
• 负责人: Patrick Lee Green
• 金额: $ 19.06万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8298808
• 关键词: Affect; Amino Acids; Animal Model; Antibodies; Biology; Cell Culture Techniques; Cells; Comparative Study; Cytotoxic T-Lymphocytes; Disease; Disease Progression; Equilibrium; Family; Future; Gene Expression; Genes; Genetic Transcription; Genome; Grant; Human; Human T-lymphotropic virus 1; Immune; Immune response; In Vitro; Individual; Infection; Infiltration; Kinetics; Knock-out; Life; Lymphocyte Activation; Maintenance; Mediating; Modeling; Molecular Cloning; Mutate; Mutation; Neurologic; Oncogene Proteins; Oncogenes; Open Reading Frames; Organ; Oryctolagus cuniculus; Pathogenesis; Pathway interactions; Play; Point Mutation; Positioning Attribute; Process; Property; Proteins; Repression; Retroviridae; Role; Symptoms; System; T-Cell Transformation; T-Lymphocyte; Taxes; Testing; Time; Tropism; Viral; Viral Genes; Viral Genome; Viral Oncogene; Viral Proteins; Virus; base; cell transformation; comparative; design; falls; human disease; in vivo; in vivo Model; insight; latent infection; leukemia; metaplastic cell transformation; mutant; neoplastic cell; novel; promoter; receptor binding; research study; response; tax Gene Products; therapeutic target; tumorigenesis; tumorigenic; virus host interaction

DESCRIPTION (provided by applicant): Human T-cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) are human tumorigenic retroviruses that encode the Tax viral oncogene, plus a newly identified possible secondary oncogene encoded by the antisense strand of the viral genome. While ~ 15 to 25 million people are infected with HTLV-1 or HTLV-2, a small portion fall victim to disease. HTLV-1 infected people eventually develop leukemia or immune mediated disease, whereas HTLV-2 disease is rare, but some infected subjects present with lymphoproliferative and neurological symptoms. Although infected individuals develop antibody and cytotoxic T-lymphocyte (CTL) responses to many of the viral proteins, the virus manages to persist throughout life. One of the viral encoded proteins, Tax, is critical for viral transcriptio and replication and has been implicated in the T-cell transformation process. Transcription from the antisense strand of the HTLV-1 genome has been described by us and others and the encoded protein termed HBZ has been shown to reduce Tax-mediated viral transcription, promote the proliferation of HTLV-1 infected cells by altering the transcriptional activity of multiple cellular factors, and be required for viral persistence in vivo. HBZ, originally thought t be unique to HTLV-1 has been hypothesized to play a role in pathogenesis. Recently, an anti-sense HTLV-2 protein (AHP-2) with limited homology to HBZ has been identified. The functional role of APH-2 in the context of a replicating virus has yet to be tested. We seek to test the hypothesis that APH-2 contributes to the balance of HTLV-2 gene transcription potentially disrupting viral replication and cell transformation in vitro and ultimately the ability of the virs to persist in an animal model. Specifically, we will determine 1) the role of APH-2 on HTLV-2 replication and T- lymphocyte transformation 2) and the effects of APH-2 on viral persistence in vivo by examining viral replication kinetics and immune response in inoculated rabbits. Importantly, since HTLV-1 and HTLV-2 are closely related retroviruses, but have distinct etiological roles in human disease, comparative studies on anti- sense proteins of HTLV-1 and HTLV-2 will provide fundamental insights into their distinct pathogenic properties. This R21 is a necessary first step to ultimately analyze the hypothesis that the anti-sense proteins in HTLV-1 and HTLV-2 affect distinct cellular factors/pathways, which determines the differences in their pathogenesis and comparative functional studies will provide important insight as to their potential as targets for therapy. PUBLIC HEALTH RELEVANCE: Approximately 15 to 25 million people worldwide are infected with human T-cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2). Although the viral Tax is the key oncogene it has become clear that persistence and pathogenesis requires contributions of other viral genes. Here we focus on a novel identified viral gene encoded by the antisense strand of the HTLV-2 genome, termed APH-2. Understanding the role APH-2 in HTLV-2 replication and persistence/latent infection will have significant implications for therapeutic targeting of these proteins and understanding how retroviruses utilize antisense encoded proteins.

描述（由申请方提供）：1型人T细胞白血病病毒（HTLV-1）和2型人T细胞白血病病毒（HTLV-2）是编码Tax病毒癌基因以及由病毒基因组反义链编码的新发现的可能的次级癌基因的人致瘤逆转录病毒。虽然约有1500万至2500万人感染了HTLV-1或HTLV-2，但一小部分人成为疾病的受害者。HTLV-1感染者最终发展为白血病或免疫介导的疾病，而HTLV-2疾病是罕见的，但一些感染的受试者表现出淋巴组织增生和神经系统症状。虽然感染个体对许多病毒蛋白产生抗体和细胞毒性T淋巴细胞（CTL）反应，但病毒设法在整个生命中持续存在。Tax是病毒编码的蛋白质之一，对病毒的转录和复制至关重要，并与T细胞转化过程有关。我们和其他人已经描述了从HTLV-1基因组的反义链的转录，并且已显示被称为HBZ的编码蛋白减少Tax介导的病毒转录，通过改变多种细胞因子的转录活性促进HTLV-1感染的细胞的增殖，并且是体内病毒持久性所需的。HBZ最初被认为是HTLV-1所特有的，现已被假设在发病机制中发挥作用。最近，已经鉴定了与HBZ具有有限同源性的反义HTLV-2蛋白（AHP-2）。APH-2在复制病毒中的功能作用还有待测试。我们试图测试的假设，APH-2有助于HTLV-2基因转录的平衡，可能破坏病毒复制和细胞转化在体外，并最终的病毒在动物模型中持续的能力。具体而言，我们将确定1）APH-2对HTLV-2复制和T淋巴细胞转化的作用2）以及APH-2对病毒体内持久性的影响，通过检查接种兔中的病毒复制动力学和免疫应答。重要的是，由于HTLV-1和HTLV-2是密切相关的逆转录病毒，但在人类疾病中具有不同的病因学作用，因此对HTLV-1和HTLV-2的反义蛋白的比较研究将提供对其不同致病特性的基本见解。该R21是最终分析HTLV-1和HTLV-2中的反义蛋白影响不同细胞因子/途径的假设的必要的第一步，这决定了它们发病机制的差异，并且比较功能研究将提供关于它们作为治疗靶点的潜力的重要见解。 公共卫生相关性：全世界约有1500万至2500万人感染人类T细胞白血病病毒1型（HTLV-1）和2型（HTLV-2）。虽然病毒Tax是关键的致癌基因，但已经清楚的是，持久性和发病机制需要其他病毒基因的贡献。在这里，我们专注于一个新的识别病毒基因编码的HTLV-2基因组的反义链，称为APH-2。了解APH-2在HTLV-2复制和持续/潜伏感染中的作用将对这些蛋白质的治疗靶向和了解逆转录病毒如何利用反义编码蛋白具有重要意义。