Experimental viral evolution at high mutation rate

高突变率下的实验性病毒进化

基本信息

批准号：
7983076
负责人：
JAMES J BULL
金额：
$ 20.72万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-01-01 至 2014-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): This work will investigate the evolution of viruses subjected to a sustained, high mutation rate. Evolution at a high mutation rate is expected to reduce population fitness by the progressive accumulation of deleterious mutations; high rates can even cause population extinction, a process known as lethal mutagenesis. This principle underlies the common use of mutagenic, drugs to treat viral infections clinically. Here, viruses (bacteriophages) will be grown in vitro at different levels of mutagenesis and the evolutionary consequences of that mutagenesis will be studied. In Aim 1, viral fitness evolution will be compared with a model predicting the amount of fitness decline based on the estimated deleterious mutation rate and viral life history parameters. Robustness of the model will be evaluated by (i) varying the mutation rate between high levels expected to cause extinction and lower levels, (ii) evolving viruses with and without recombination, and (iii) studying viruses with RNA genomes and others with DNA genomes. A preliminary study already observed the evolution of much higher viral fitness than predicted (due to viral adaptation), and special attention will be given to the factors contributing to viral adaptation during mutagenic treatment. In Aim 2, populations of viruses surviving mutagenic treatment will be assayed for elevated frequencies of beneficial phenotypes (e.g., ability to grow on inhibitors), to address whether failed lethal mutagenesis might accelerate evolution in counter-productive ways. In Aim 3, viral populations that survived mutagenic treatment and isolates from those populations will be evolved in the absence of mutagenesis. The question here is how long the mutational load from mutagenic treatment will depress fitness below wild-type levels after treatment is stopped. Collectively, these studies should provide a foundation for interpreting and designing efforts at lethal mutagenesis in vivo. PUBLIC HEALTH RELEVANCE: Some antiviral drugs elevate the mutation rate of the virus. It has been proposed that the elevated mutation rate contributes to curing the infection (extinction through 'lethal mutagenesis'), but the mutagenic drugs are often not successful. The work here will investigate the foundations of lethal mutagenesis and whether the elevated mutation rate might instead lead to enhanced viral evolution.

描述（由申请人提供）：这项工作将研究遭受持续、高突变率的病毒的进化。高突变率的进化预计会因有害突变的逐渐积累而降低种群适应性；高比率甚至会导致种群灭绝，这一过程被称为致命诱变。这一原则是临床上常用诱变药物治疗病毒感染的基础。在这里，病毒（噬菌体）将以不同的诱变水平在体外生长，并将研究该诱变的进化后果。在目标 1 中，病毒适应度进化将与基于估计的有害突变率和病毒生命史参数预测适应度下降量的模型进行比较。该模型的稳健性将通过以下方式进行评估：(i) 改变预期导致灭绝的高水平和较低水平之间的突变率，(ii) 进化病毒（有或没有重组），以及 (iii) 研究具有 RNA 基因组的病毒和其他具有 DNA 基因组的病毒。一项初步研究已经观察到病毒适应度远高于预期的进化（由于病毒适应），并且将特别关注诱变治疗期间促进病毒适应的因素。在目标 2 中，将对在诱变处理中幸存的病毒群体进行检测，以确定其有益表型频率的升高（例如，在抑制剂上生长的能力），以解决失败的致死诱变是否可能以适得其反的方式加速进化。在目标 3 中，在诱变处理中幸存下来的病毒群体以及从这些群体中分离出来的病毒群体将在没有诱变的情况下进化。这里的问题是，在治疗停止后，诱变治疗产生的突变负荷将在多长时间内将健康水平降低到野生型水平以下。总的来说，这些研究应该为解释和设计体内致死突变的工作提供基础。公共卫生相关性：一些抗病毒药物会提高病毒的突变率。有人提出，突变率升高有助于治愈感染（通过“致死诱变”灭绝），但诱变药物往往不成功。这里的工作将研究致命突变的基础，以及突变率的升高是否可能导致病毒进化增强。