Structure-Function Analyses of HIV Rev and HTLV Rex

描述(由申请人提供)：目前的艾滋病毒-艾滋病和相关疾病研究合作(FIRCA)申请提出的研究将加强美国俄亥俄州立大学(帕特里克·格林博士)和意大利帕多瓦大学(唐娜·达戈斯蒂诺博士)两个高生产率研究小组之间新开发的合作。在首席研究人员参加了2001年6月25日至29日在爱尔兰都柏林举行的“第十届人类逆转录病毒学国际会议：HTLV和相关病毒”之后，各参与实验室之间出现了联合研究项目。会议期间讨论了如下提案中概述的联合项目。继续进行这些富有成效的交流的关键是提供资金，使合作为美国调查人员的利益而成熟，并使意大利帕多瓦大学实验室的研究能力得以扩大。拟议的研究将结合在每个机构建立的资源，用于两个参与者的集体利益。HIV和HTLV是一种复杂的逆转录病毒，其表达受病毒调节蛋白Tat和REV(HIV)和Tax和Rex(HTLV)控制。我们的研究实验室共同开展了基础研究，以确定每种病毒的调控蛋白的作用，并处于独特的地位，可以确定这些类似的调控蛋白如何影响这些复杂逆转录病毒的基因表达和复制。格林博士的研究小组已经证明，Tax对细胞转化是必不可少的，并发现了Rex-2的一个新的磷酸化结构域，它可以调节其功能。达戈斯蒂诺博士已经证明，通过选择性剪接，HTLV-2可能会产生截短形式的Rex-2，称为x-III蛋白，作为全长Rex-2的抑制物。最近，她的团队证明了REV中一个环状区域的功能重要性，该区域影响了蛋白质的几个对其功能至关重要的属性。我们提出的合作研究的具体目标是：1)探索磷酸化在x-III蛋白活性中的作用，并研究它们对HTLV-2复制的影响；以及2)通过蛋白激酶C介导的丝氨酸残基的磷酸化和环区Pro的异构化来研究REV的构象和功能的控制。拟议中的与艾滋病相关的FIRCA结合起来的设施和专业知识是独特的、富有成效的，并履行了Fogarty国际中心支持美国和外国之间合作研究的使命。

DESCRIPTION (provided by applicant): The present HIV-AIDS and Related Illnesses Research Collaboration (FIRCA) application proposes studies that will strengthen a newly developed collaboration between two highly productive research groups at The Ohio State University, USA (Dr. Patrick Green) and the University of Padova, Italy (Dr. Donna D'Agostino). Joint research projects between the participating laboratories emerged following the principal investigators' participation in the "10th International Conference on Human Retrovirology: HTLV and Related Viruses held in Dublin, Ireland, June 25-29, 2001. During the meeting, joint projects were discussed as outlined in the following proposal. Critical to the continuation of these productive exchanges are funds to allow the collaborations to mature for the benefit of the United States investigator and to enable expansion of the research capacity of the laboratory at the University of Padova, Italy. The proposed research will combine the resources that are established in each institution to be used for the collective benefit of both participants. HIV and HTLV are complex retroviruses whose expression is controlled by the viral regulatory proteins Tat and Rev (HIV) and Tax and Rex (HTLV). Together, our research laboratories have performed basic studies to define the role of regulatory proteins of each virus and are in a unique position to determine how these analogous regulatory proteins influence gene expression and replication of these complex retroviruses. Dr. Green's research group has shown that Tax is essential for cellular transformation and has identified a novel phosphorylation domain of Rex-2 that regulates its function. Dr. D'Agostino has shown that, through altemative splicing, HTLV-2 may produce truncated forms of Rex-2 termed x-III proteins that act as repressors of full-length Rex-2. More recently, her group demonstrated the functional importance of a loop region in Rev that influences several properties of the protein that are essential to its function. Specific aims that will be addressed in our proposed collaborative research are: 1) to explore the role of phosphorylation in the activity of the x-III proteins and examine their effect on HTLV-2 replication; and 2) to investigate the control of Rev's conformation and function by protein kinase C-mediated phosphorylation at serine residues and by isomerization of prolines in the loop region. The combined facilities and expertise brought together by the proposed AIDS-related FIRCA are unique, productive, and fulfill the mission of the Fogarty International Center to support collaborative research between the United States and foreign countries.