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，包括快速遗传的能力 响应不同的选择压力而发生变化；宿主细胞受体的使用发生变化的能力；和 整合到宿主物种基因组中并代代相传的能力 作为内源性原病毒。在之前的项目期间，我们研究了逆转录病毒的所有这些方面 进化：我们通过分析一种不寻常的突变体来研究 env 基因的进化机制。 将 ALV 的宿主范围从鸡扩展到鹌鹑、狗，甚至人类细胞。我们已经隔离并 研究了一种不寻常的小鼠内源性原病毒，它似乎占据了特殊的系统发育位置 小鼠和非小鼠物种之间。我们广泛分析了人类的共同进化 它们的内源性原病毒，特别是最近插入的 HERV-K 家族。我们开发了 复制病毒种群进化的复杂数学模型，描述了 有害突变积累（或丢失）的突变、选择、漂移、连锁和重组。 未来的工作将实现以下目标。 1. 逆转录病毒包膜基因如何进化以利用新的 受体并改变其他重要特性？我们将使用我们的扩展宿主范围突变体来测试 这个过程的具体假设。 2. 人类的功能和致病特性是什么 内源性逆转录病毒，特别是 HERV-K？我们能分离出传染性病毒吗？他们的表达方式还是 重新融入社会与恶性肿瘤有关吗？ 3. 突变、选择的力量有多重要？ 重组和漂移结合直接逆转录病毒进化？我们将结合数学和体外 病毒复制建模以测试特定的进化模型。 相关性：除了作为基本发现工具的不可估量的价值外，逆转录病毒进化还具有 对公共卫生产生重要影响。在最近的历史中，一些逆转录病毒已经进化到可以使用 人类作为宿主，会带来毁灭性的后果。此外，病毒在给定宿主内的进化可以 具有重要的后果，例如使用不同的受体、毒力增加或耐药性 药物。了解这种演变在我们过去是如何发生的以及它是如何在简单的情况下发生的 模型将使我们更好地准备应对此类事件的发生。