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细胞生长和活力。然而，有 现在有许多病毒利用的例子，其中延长核糖体 被编程为将其翻译阅读框在 5' 中移动一个碱基 方向。这个过程称为程序性-1核糖体移码。 程序化-1核糖体移码被真核生物独特地利用 病毒，使其成为开发抗病毒药物的引人注目的目标。的 人类免疫缺陷病毒 1 型 (HIV-1) 利用编程的 -1 核糖体 移码以从单个蛋白合成 gag 和 gag-pol 蛋白 成绩单。他们一直在研究顺式作用元件 决定程序化-1核糖体移码的反式作用因子 酿酒酵母的效率。使用双链 L-A病毒系统，他们已经表明，堵嘴与堵嘴的比例发生微小变化 通过改变移码效率合成的 gag-pol 会导致损失 杀手病毒。这些发现使他们提出了这样一个概念： 可以识别出改变程序化效率的抗病毒药物 移码而不显着影响整体蛋白质合成。他们 已经使用酵母杀手病毒成功证明了这一原理 系统作为模型，最近，以哺乳动物细胞中的艾滋病毒为模型。基于 在这些研究中，他们提出表征程序化-1移码 HIV-1 的研究目标是开发这种病毒的特异性机制作为目标 用于抗病毒干预。本次资助中提出的实验目的 建议将描述促进高效的序列的特征 HIV-1 中的移码并确定改变移码的影响 HIV 产生的效率。他们还将进一步确定是否 改变程序化-1移码并促进丢失的假定化合物 杀手病毒还将减少或消除艾滋病毒的产生。附加 影响程序化移码的化合物也将被鉴定。 最后，他们将在分子水平上研究化合物如何影响 编程移帧功能。他们的长期目标是发展 影响移码达到原理证明的化合物 已经建立，并且针对该过程的抗病毒药物将被 随后开发用于临床。

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.