Role of viral HBZ in HTLV-1 replication and pathogenesis

描述（由申请人提供）：据估计，全球约有1500万至2500万人感染人类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相关。虽然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，但病毒设法在整个生命中持续存在。Tax是一种病毒调节蛋白，对病毒的转录和复制至关重要，并已明确参与体外T淋巴细胞转化和体内肿瘤发生。已经描述了由前病毒基因组的反义链编码的称为HBZ的HTLV-1蛋白。过表达研究表明，HBZ是一种核b-ZIP蛋白，其通过与CREB-2和AP-1复合物的其他b-ZIP蛋白异源二聚化来下调Tax诱导的HTLV-1病毒转录。的功能作用 HBZ在复制病毒中的作用及其对病毒复制和病毒诱导的细胞凋亡的影响 体外永生化/转化和体内病毒复制动力学尚未进行测试。两 提出了具体的目的来检验HBZ有助于HTLV-1基因转录的调节平衡的假设，其可能在体外破坏病毒复制和细胞转化，并最终破坏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生物学和发病机制的贡献。这些研究可能最终提供一种治疗靶向这种蛋白质的方法，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.