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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：人类T细胞白血病病毒1型（HTLV-1）和2型（HTLV-2）是人类的肿瘤逆转录病毒，它们编码税收病毒癌基因，再加上新近鉴定的二次癌元，由病毒基因组的反义链编码。〜15至2500万人感染了HTLV-1或HTLV-2，而一小部分是疾病的受害者。 HTLV-1感染的人最终患有白血病或免疫介导的疾病，而HTLV-2疾病很少见，但是一些受感染的受试者出现淋巴细胞增生性和神经系统症状。尽管受感染的个体发展了对许多病毒蛋白的抗体和细胞毒性T淋巴细胞（CTL）反应，但该病毒始终持续存在。病毒编码的蛋白质之一是税收，对于病毒转录和复制至关重要，并且与T细胞转化过程有关。美国和其他人已经描述了HTLV-1基因组反义链的转录，已证明称为HBz的编码蛋白可以减少税收介导的病毒转录，促进HTLV-1感染细胞的增殖，通过改变多个细胞因子的转录活性，并在VIVO中进行病毒持久性所需。 HBz最初认为HTLV-1是独有的，已假设在发病机理中发挥作用。最近，已经确定了与HBZ同源性有限的抗敏感性HTLV-2蛋白（AHP-2）。 APH-2在复制病毒中的功能作用尚未测试。我们试图检验以下假设：APH-2有助于HTLV-2基因转录的平衡，可能会破坏体外病毒复制和细胞转化，并最终使VIRS在动物模型中持续存在的能力。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）以及通过检查接种兔中的病毒复制动力学和免疫反应，APH-2对体内病毒持久性的作用。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明显的病因作用，因此对HTLV-1和HTLV-2抗感觉蛋白的比较研究将提供对其独特的致病特性的基本见解。该R21是最终分析HTLV-1和HTLV-2中的抗震动蛋白会影响不同细胞因子/途径的假说的必要第一步，这决定了其发病机理和比较功能研究的差异，将为其潜在的治疗靶标提供重要的见解。公共卫生相关性：全球大约有15至2500万人感染了人类T细胞白血病病毒1型（HTLV-1）和2型（HTLV-2）。尽管病毒税是关键的致癌基因，但很明显，持久性和发病机理需要其他病毒基因的贡献。在这里，我们专注于一种新型的被称为APH-2的HTLV-2基因组的反义链编码的病毒基因。了解APH-2在HTLV-2复制和持久性/潜在感染中的作用将对这些蛋白质的治疗靶向产生重大影响，并了解逆转录病毒如何利用反义编码的蛋白质。