Mechanisms of Post-Transcriptional Control by HTLV p28

对逆转录病毒的研究已经导致了重要的发现，并导致了对基本细胞的了解。 生物学，包括细胞信号传导机制、基因的转录和转录后控制 表达，并最终导致细胞转化和癌症。项目2关注人类T细胞 白血病病毒（HTLV）是一种主要与白血病相关的病毒，是一种非常有价值的逆转录病毒模型 诱发癌症。这个高度互动的项目的长期目标是了解病毒宿主 转录后调节病毒复制的相互作用。我们已经证明，转录后 阳性HTLV调节蛋白，雷克斯，以前的应用的重点，不直接有助于 体外细胞转化。我们通过合作扩展了我们的工作，以确定和表征 HTLV-1和HTLV-2相关的辅助基因产物的新功能，其在转录后起作用， 税收和雷克斯的负调节器。我们的令人兴奋的新功能分配给p28和p30作为转录后 控制调节器提供了当前提议的基础。我们假设p28- 介导的T淋巴细胞中病毒复制的减少和/或T淋巴细胞的增殖可以允许 这些细胞的存活，允许逃避免疫识别，这将是一致的， HTLV辅助蛋白在体内病毒持久性中的关键作用。我们试图定义转录后 p28抑制活性的机制，通过1）鉴定和表征功能结构域， p28的生物化学性质，2）确定p28 mRNA的一级序列和结构/功能 靶，和3）确定p28在病毒复制，淋巴细胞活化/转化， 以及病毒在体内的持久性。了解转录后的确切作用机制 对p28/p30的控制最终将提供一种治疗靶向这些蛋白质的手段， HTLV在主机中的持久性。重要的是这个PPG，我们的研究结果将有助于了解HTLV如何 改变T细胞生理学，从而深入了解调节病毒复制的机制， 淋巴细胞活化和细胞转化阶段。

The study of retroviruses have resulted in important discoveries and has lead to insights into basic cell biology including mechanisms of cell signaling, transcriptional and post transcriptional control of gene expression, and ultimately cellular transformation and cancer. Project 2 focuses on the human T-cell leukemia virus (HTLV) which is associated primarily with leukemia and highly valuable model of retrovirus induced cancer. The long-term objective of this highly interactive project is to understand virus-host interactions that regulate viral replication post-transcriptionally. We have shown that the post-transcriptional positive HTLV regulatory protein, Rex, the focus of the previous application, does not directly contribute to cellular transformation in vitro. We extended our work through collaboration to identify and characterize a novel function of HTLV-1 and HTLV-2 related accessory gene products that act post-transcriptionally as negative regulators of both Tax and Rex. Our exciting new function assigned to p28 and p30 as posttranscriptional control regulators provide the basis for the current proposal. We hypothesize that p28- mediated reduction of viral replication in T-lymphocytes and/or the proliferation of T-lymphocytes may permit survival of these cells by allowing escape from immune recognition, which would be consistent with the critical role of HTLV accessory proteins in viral persistence in vivo. We seek to define the post-transcriptional mechanisms of p28 repressive activity by 1) identifying and characterizing functional domains and biochemical properties of p28, 2) determining the primary sequence and structure/function of the p28 mRNA target, and 3) determining the contribution of p28 in viral replication, lymphocyte activation/transformation, and persistence of the virus and in vivo. Understanding the exact mechanism of action of post-transcriptional control of p28/p30 ultimately will provide a means for therapeutic targeting of these proteins to eradicate HTLV persistence in the host. Important to this PPG, our findings will contribute to understand how HTLV alters T-cell physiology and thus gain insight into the mechanisms of regulating viral replication and the early phases of lymphocyte activation and cellular transformation.