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

描述(申请人提供)：人类T细胞白血病病毒1型(HTLV-1)和2型(HTLV-2)是人类致癌逆转录病毒，编码Tax病毒癌基因，以及新发现的由病毒基因组的反义链编码的可能的次级癌基因。虽然约有1500万至2500万人感染了HTLV-1或HTLV-2，但有一小部分人成为疾病的受害者。HTLV-1感染者最终会发展成白血病或免疫介导性疾病，而HTLV-2病很少见，但一些感染者会出现淋巴增殖和神经症状。尽管感染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。病毒编码蛋白之一，TAX，对病毒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HTLV-1基因组反义链的转录，编码的HBZ蛋白被证明减少了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感染细胞的增殖，并在体内维持病毒的持续。HBZ最初被认为不是HTLV-1所特有的，现已被认为在发病机制中发挥了作用。最近发现了一个与HBZ同源性有限的反义HTLV-2蛋白(AHP-2)。APH-2在复制病毒的背景下的功能作用还有待测试。我们试图测试APH-2有助于HTLV-2基因转录的平衡，潜在地扰乱病毒复制和细胞体外转化，并最终在动物模型中持续存在的能力的假设。具体地说，我们将通过检测病毒复制动力学和免疫反应来确定1)APH-2对HTLV-2复制和T淋巴细胞转化的作用2)以及APH-2对体内病毒持久性的影响。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原学作用，因此对HTLV-1和HTLV-2反义蛋白的比较研究将为了解它们不同的致病特性提供基础。这个R21是最终分析HTLV-1和HTLV-2中的反义蛋白影响不同的细胞因子/途径的假说的必要的第一步，这决定了它们在发病机制上的差异，比较功能研究将为它们作为治疗靶点的潜力提供重要的见解。

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.