Role of viral HBZ in HTLV-1 replication and pathogenesis

病毒 HBZ 在 HTLV-1 复制和发病机制中的作用

• 批准号: 6902189
• 负责人: Patrick Lee Green
• 金额: $ 18.69万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6902189
• 关键词: cellular immunity; clinical research; gene mutation; genetic regulation; genetic transcription; host organism interaction; human T cell lymphotropic virus type 1; human subject; humoral immunity; immune response; immunofluorescence technique; laboratory rabbit; mixed tissue /cell culture; molecular cloning; molecular pathology; protein structure function; virus cytopathogenic effect; virus genetics; virus protein; virus replication

DESCRIPTION (provided by applicant): It is estimated that approximately 15 to 25 million people worldwide are infected with human T-cell leukemia virus type 1 (HTLV-1). HTLV-1 infection is associated primarily with leukemia and neurological disease in a small percentage of infected patients. Although infected patients develop antibody and cytotoxic Tlymphocyte (CTL) responses to many of the viral proteins, the virus manages to persist throughout life. One of the viral regulatory proteins, Tax, is critical for viral transcription and replication and has been clearly implicated in T-lymphocyte transformation in vitro and oncogenesis in vivo. An HTLV-1 protein termed HBZ, encoded by the anti-sense strand of the proviral genome has been described. Over expression studies have shown that HBZ is a nuclear b-ZIP protein that down regulates Tax induced HTLV-1 viral transcription by hetero-dimerizing with CREB-2 and other b-ZIP proteins of the AP-1 complex. The functional role of HBZ in the context of a replicating virus and its contribution to viral replication and viral-induced cellular Immortalization / transformation in vitro and on viral replication kinetics in vivo has yet to be tested. Two specific aims are proposed to test the hypothesis that HBZ contributes to the regulatory balance of HTLV-1 gene transcription potentially disrupting viral replication and cell transformation in vitro and ultimately the ability of the virus to persist in an animal model. These studies will determine for the first time the contribution of HBZ to HTLV-1 biology and pathogenesis. These studies could ultimately provide a means for therapeutic targeting of this protein to eradicate HTLV-1 persistent infection in the host.

描述（由申请人提供）：据估计，全世界约有15至2500万人感染了人类T细胞白血病病毒1型（HTLV-1）。 HTLV-1感染主要与一小部分感染患者的白血病和神经系统疾病有关。尽管受感染的患者会发展出对许多病毒蛋白的抗体和细胞毒性胞球细胞（CTL）反应，但该病毒在一生中都持续存在。一种病毒调节蛋白之一，税收对病毒转录和复制至关重要，并且在体外和体外的T淋巴细胞转化和体内肿瘤发生都显然与T-淋巴细胞转化有关。已经描述了一种称为HBz的HTLV-1蛋白，该蛋白已被描述为病毒基因组的抗义链编码。过度表达的研究表明，HBZ是一种核B-ZIP蛋白，通过用CREB-2和AP-1复合物的其他B-ZIP蛋白异异性二进制来调节税收诱导的HTLV-1病毒转录。功能的作用 在复制病毒的背景下，HBZ及其对病毒复制和病毒诱导的细胞的贡献 体外和病毒复制动力学体内的永生 /转化尚未测试。二 提出了具体目的，以检验HBz有助于HTLV-1基因转录的调节平衡的假设，可能会破坏体外病毒复制和细胞转化，并最终导致病毒在动物模型中持续存在的能力。这些研究将首次确定HBZ对HTLV-1生物学和发病机理的贡献。这些研究最终可以提供一种治疗性靶向该蛋白质以根除宿主中HTLV-1持续感染的方法。