Retrovirus Evolution

逆转录病毒进化

• 批准号: 7780021
• 负责人: JOHN M COFFIN
• 金额: $ 66.63万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-05 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7780021
• 关键词: Address; Affect; Antigenic Variation; Antiviral Agents; Area; Back; Biological Assay; Biology; Canis familiaris; Cells; Chickens; Complex; DNA Sequence Rearrangement; Disease; Drug resistance; Employee Strikes; Event; Evolution; Exhibits; Family; Fossils; Future; Gene Transduction Agent; Generations; Genes; Genetic Phenomena; Genetic Polymorphism; Genetic Recombination; Genetic Transcription; Genetic Variation; Genome; Genomic Instability; HERVs; HIV; Human; In Vitro; Infection; Investigation; Laboratories; Left; Location; Malignant Neoplasms; Mediating; Modeling; Mus; Mutation; Oncogenes; Phylogenetic Analysis; Population; Population Sizes; Primates; Process; Property; Proteins; Proviruses; Public Health; Quail; Receptor Cell; Recording of previous events; Relative (related person); Resistance; Retroviridae; Role; Science; Specificity; Subgroup; System; Testing; Time; Vaccine Design; Variant; Viral; Virulence; Virus; Virus Replication; Virus-like particle; Work; cell type; drug development; env Genes; gene therapy; hazard; in vitro Model; in vivo; interest; malignant breast neoplasm; mathematical model; member; mutant; pressure; receptor; receptor binding; research study; response; theories; tool

Retroviruses exhibit a wealth of evolutionary phenomena, including the ability to undergo rapid genetic change in response to varying selective pressure; the ability to vary in the use of host cell receptors; and the ability to become integrated in the genome of their host species and passed down through the generations as endogenous proviruses. In the prior project period, we have studied all these aspects of retrovirus evolution: We have looked at the mechanism of evolution of env genes by analyzing an unusual mutant that extends the host range of ALV beyond chicken, to quail, dog, and even human cells. We have isolated and studied an unusual mouse endogenous provirus that appears to occupy a special phylogenetic location between mouse and non mouse species. We have extensively analyzed the coevolution of humans and their endogenous proviruses, particulary the relatively recently inserted HERV-K family. We have developed sophisticated mathematical models for the evolution of replicating virus populations, describing the effects of mutation, selection, drift, linkage, and recombination on the accumulation (or loss) of deleterious mutations. Future work will address the following aims. 1. How do retroviral envelope genes evolve to use new receptors and to alter other important properties? We will use our extended host range mutants to test specific hypotheses for this process. 2. What are the functional and pathogenic properties of human endogenous retroviruses, particularly HERV-K? Can we isolate infectious virus? Is their expression or reintegration associated with malignancy? 3. How do important the forces of mutation, selection, recombination, and drift combine to direct retrovirus evolution? We will combine mathematical and in vitro modelling of virus replication to test specific evolutionary models. Relevance: In addition to its inestimable value as a tool of basic discovery, retrovirus evolution has important consequences for public health. In recent history, several retroviruses have evolved to use humans as hosts, with devastating consequences. Furthermore, evolution of viruses within a given host can have important consequences, such as use of different receptors, increased virulence, or resistance to drugs. Understanding of both how this evolution has occurred in our past and how it occurs in simple models will leave us better prepared to deal with such events as they happen.

逆转录病毒表现出丰富的进化现象，包括经历快速遗传的能力 改变选择性压力的变化；在使用宿主细胞受体方面有所不同的能力；和 能够融入其宿主物种的基因组并传播到世代相传的能力 作为内源性病毒。在以前的项目期间，我们研究了逆转录病毒的所有这些方面 进化：我们通过分析一个异常突变体来研究ENV基因进化的机制。 将ALV的宿主范围扩展到鸡，鹌鹑，狗甚至人类细胞。我们孤立了， 研究了一个异常的小鼠内源性病毒，该病毒似乎占据了特殊的系统发育位置 在小鼠和非小鼠物种之间。我们已经广泛分析了人类的共同进化 他们的内源性病毒，特别是最近插入的HERV-K家族。我们已经发展了 复制病毒群体演变的复杂数学模型，描述了 关于有害突变的积累（或损失）的突变，选择，漂移，连锁和重组。 未来的工作将解决以下目标。 1。逆转录病毒信封基因如何发展为使用新的 受体并改变其他重要特性？我们将使用扩展的宿主射程突变体进行测试 此过程的特定假设。 2。人的功能和致病性能是什么 内源性逆转录病毒，尤其是HERV-K？我们可以隔离传染病吗？是他们的表情还是 与恶性肿瘤有关的重新整合？ 3。突变，选择的力量如何 重组和漂移合并以直接逆转录病毒进化？我们将结合数学和体外 对病毒复制的建模以测试特定的进化模型。 相关性：除了它作为基本发现工具的不可估量的价值外，逆转录病毒的进化还具有 对公共卫生的重要后果。在最近的历史中，几种逆转录病毒已经进化为使用 人类作为宿主，带来毁灭性的后果。此外，给定宿主内病毒的演变可以 具有重要的后果，例如使用不同受体，增加毒力或对 毒品。了解这种演变如何发生在我们的过去以及它如何发生的情况下 模型将使我们更好地准备应对这些事件的发生。