HIV FRAMESHIFTING--FROM BIOLOGY TO THERAPEUTICS

描述(改编自申请人的摘要)：核糖体的能力 保持正确的翻译阅读框架是 蛋白质合成的完整性以及对细胞生长和活力的影响。然而，在那里 现在有许多病毒利用的例子，其中拉长的核糖体 被编程将他们的翻译阅读框架在5‘中移动一个基数 方向。这一过程被称为程序化核糖体移帧。 核糖体程序化移帧被真核生物所独有 病毒，使其成为开发抗病毒药物的引人注目的目标。这个 人类免疫缺陷病毒1型(HIV-1)利用程序化的-1核糖体 移码以合成Gag和Gag-Poll蛋白 文字记录。他们一直在调查顺位行动分子和 决定程序化-1核糖体移码的反式作用因素 酿酒酵母中的效率。使用双链 L--一种病毒系统，他们已经表明，插嘴的比率发生了微小的变化 通过改变移帧效率合成的GAG-POL导致 致命的病毒。这些发现使他们形成了这样一种概念 可以确定抗病毒药物可以改变程序化的效率 在不显著影响全球蛋白质合成的情况下进行帧转移。他们 已经成功地用酵母杀手病毒证明了这一原理 系统作为模型，最近在哺乳动物细胞中发现了艾滋病毒。基于 这些调查，他们建议将编程移帧的特征 以开发这种病毒特异性机制为目标的HIV-1 进行抗病毒干预。这项资助中提出的实验的目的 建议将对促进高效的序列进行表征 HIV-1中的移帧和改变移帧的影响 提高艾滋病毒生产的效率。他们还将进一步确定是否 可能的化合物会改变程序化的移帧和促进蛋白质的丢失 这种致命病毒还将减少或消除艾滋病毒的产生。其他内容 影响程序移帧的化合物也将被识别。 最后，他们将在分子水平上研究化合物如何影响 程控移帧功能。他们的长期目标将是发展 影响框架移动到原理证明所具有的点的化合物 已经建立，针对这一过程的抗病毒药物将是 后来开发出来用于临床。

DESCRIPTION (Adapted from applicant's abstract): The ability of ribosomes to maintain the correct translational reading frame is fundamental to the integrity of protein synthesis and to cell growth and viability. However, there are now a number of examples utilized by viruses in which elongating ribosomes are programmed to shift their translational reading frame one base in the 5' direction. This process is called programmed -1 ribosomal frame-shifting. Programmed -1 ribosomal frame-shifting is utilized uniquely by eucaryotic viruses, making it a compelling target for developing antiviral agents. The human immunodeficiency virus type 1 (HIV-1) utilizes a programmed -1 ribosomal frameshift to synthesize both the gag and gag-pol proteins from a single transcript. They have been investigating the cis-acting elements and trans-acting factors that determine programmed -1 ribosomal frame-shifting efficiencies in the yeast Saccharomyces cerevisiae. Using the double-stranded L-A virus system, they have shown that small changes in the ratio of the gag to gag-pol synthesized by altering frame-shifting efficiency leads to a loss of the killer virus. These findings have led them to develop the concept that antiviral agents can be identified that alter the efficiency of programmed frame-shifting without dramatically affecting global protein synthesis. They have successfully demonstrated this principle using the yeast killer virus system as the model, and more recently, with HIV in mammalian cells. Based on these investigations, they propose to characterize programmed -1 frame-shifting in HIV-1 with the goal of developing this virus specific mechanism as a target for antiviral intervention. The aims of the experiments proposed in this grant proposal will be to characterize the sequences that promote efficient frame-shifting in HIV-1 and to determine the affects of altering frame-shifting efficiency on HIV production. They will also characterize further determine if putative compounds that alter programmed -1 frame-shifting and promote loss of the killer virus will also reduce or eliminate HIV production. Additional compounds that affect programmed frame-shifting will also be identified. Finally, they will investigate at the molecular level how compounds that affect programmed frame-shifting function. Their long-term goal will be to develop compounds that affect frame-shifting to the point that proof of principle has been established and antiviral agents targeting this process will be subsequently developed for clinical use.