Role of viral HBZ in HTLV-1 replication and pathogenesis

描述(申请人提供)：据估计，全球约有1500万至2500万人感染了人类T细胞白血病病毒1型(HTLV-1)。HTLV-1感染主要与白血病和一小部分感染患者的神经系统疾病有关。虽然受感染的患者对许多病毒蛋白产生抗体和细胞毒性T淋巴细胞(CTL)反应，但病毒设法在一生中持续存在。病毒调节蛋白之一Tax是病毒转录和复制的关键蛋白之一，在体外与T淋巴细胞转化和体内肿瘤发生密切相关。一种被称为HBZ的HTLV-1蛋白，由前病毒基因组的反义链编码。过表达研究表明，HBZ是一种核内b-ZIP蛋白，通过与CREB-2和AP-1复合体的其他b-ZIP蛋白异源二聚体下调TAX诱导的HTLV-1病毒转录。的职能作用 复制病毒背景下的HBZ及其对病毒复制和病毒诱导的细胞的贡献 体外永生化/转化和体内病毒复制动力学尚未得到验证。二 针对HBZ有助于HTLV-1基因转录的调节平衡、潜在地扰乱病毒复制和体外细胞转化以及最终病毒在动物模型中持续存在的能力这一假说，提出了具体的目标。这些研究将首次确定HBZ对HTLV-1生物学和致病机制的贡献。这些研究最终可能为该蛋白的治疗靶向提供一种手段，以根除宿主中的HTLV-1持续感染。

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.