Experimental viral evolution at high mutation rate

高突变率下的实验性病毒进化

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/7983076
• 关键词: Address; Aftercare; Animals; Antiviral Agents; Attention; Back; Bacteriophages; Biological Assay; Clinical Virology; DNA; DNA Viruses; Depressed mood; Development; Drug usage; Evolution; Experimental Models; Extinction (Psychology); Foundations; Frequencies; Generations; Genetic Recombination; Genome; Health; Human; Immune; Immune system; In Vitro; Incidence; Infection; Lead; Literature; Measures; Modeling; Mutagenesis; Mutagens; Mutate; Mutation; Outcome; Patients; Pharmaceutical Preparations; Phenotype; Population; Process; Property; RNA; Resistance; Risk; Staging; System; Technology; Testing; Transcend; Treatment Failure; Vaccines; Viral; Virus; Virus Diseases; Work; base; combat; design; fitness; in vivo; inhibitor/antagonist; life history; mathematical model; new technology; novel; public health relevance; success; tissue tropism; viral RNA; virology

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）：这项工作将调查受到持续高突变率的病毒的演变。高突变率的进化有望通过有害突变的进行性积累来降低种群适应性；高率甚至会导致人口灭绝，这一过程称为致命诱变。该原理是诱变，药物在临床上治疗病毒感染的普遍用途。在这里，将在不同水平的诱变水平上在体外生长病毒（噬菌体），该诱变的进化后果将被研究。在AIM 1中，将将病毒适应性演变与预测基于估计有害突变率和病毒寿命参数的模型进行比较。该模型的鲁棒性将通过（i）改变预期导致灭绝和较低水平的高水平之间的突变率，（ii）随着和没有重组的形式发展病毒，以及（iii）用RNA基因组和其他DNA基因组研究病毒。一项初步研究已经观察到比预测的更高的病毒适应性的演变（由于病毒适应），并且将特别注意在诱变治疗过程中导致病毒适应的因素。在AIM 2中，将测定幸存诱变治疗的病毒种群，以提高有益表型的频率升高（例如，在抑制剂上生长的能力），以解决失败的致命诱变是否可能以适得其反生产的方式加速进化。在AIM 3中，在没有诱变的情况下，将进化在诱变治疗中幸存下来的病毒群体和分离株。这里的问题是，诱变治疗的突变负荷将在停止治疗后将适应性降低到野生型水平以下。总的来说，这些研究应为在体内致命诱变的解释和设计努力提供基础。 公共卫生相关性：一些抗病毒药提高了病毒的突变率。已经提出，升高的突变率有助于治愈感染（通过“致命诱变”消灭），但诱变药物通常不成功。这里的工作将研究致命诱变的基础，以及升高的突变率是否可能导致病毒进化增强。