Mechanisms of Post-Transcriptional Control by HTLV p28

对逆转录病毒的研究导致了重要的发现，并导致了对基本细胞的深入了解 生物学包括细胞信号机制、基因转录和转录后控制 表达，最终导致细胞转化和癌症。项目2的重点是人类T细胞 白血病病毒(HTLV)，主要与白血病有关，是极具价值的逆转录病毒模型 诱发癌症。这个高度互动项目的长期目标是了解病毒宿主 转录后调控病毒复制的相互作用。我们已经证明了转录后的 HTLV阳性调节蛋白，Rex，是先前应用的重点，并不直接有助于 体外细胞转化。我们通过合作扩展了我们的工作，以确定和描述 HTLV-1和HTLV-2相关辅助基因产物转录后的新功能 税收和雷克斯的负面监管机构。我们令人兴奋的新功能被分配给P28和P30作为转录后 控制监管机构为当前的提议提供了基础。我们假设p28- 介导的T淋巴细胞病毒复制的减少和/或T淋巴细胞的增殖可能允许 通过允许逃避免疫识别来存活这些细胞，这将与 HTLV辅助蛋白在体内病毒持续存在中的关键作用。我们试图定义转录后基因 P28抑制活性的机制：1)识别和表征功能结构域和 P28的生化性质，2)确定p28基因的一级序列和结构/功能 靶点，以及3)确定p28在病毒复制、淋巴细胞激活/转化中的作用， 以及病毒在体内和体内的持久性。理解转录后转录的确切作用机制 对p28/p30的控制最终将为治疗靶向消除这些蛋白提供一种手段。 HTLV在宿主中的持久性。重要的是，我们的发现将有助于理解HTLV是如何 改变T细胞生理学，从而深入了解调节病毒复制的机制和早期 淋巴细胞活化和细胞转化的阶段。

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.