Retrovirus Evolution

逆转录病毒进化

• 批准号: 8239504
• 负责人: JOHN M COFFIN
• 金额: $ 67.25万
• 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 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239504
• 关键词: Antiviral Agents; Biochemical; Biological Models; Canis familiaris; Cells; Chickens; Development; Drug resistance; Elements; Event; Evolution; Exhibits; Future; Generations; Genes; Genetic Recombination; Genome; HERVs; HIV; Human; Human Genome; Instruction; Integration Host Factors; Left; Modeling; Mus; Mutation; Pathogenesis; Pathway interactions; Population; Property; Proviruses; Public Health; Quail; Receptor Cell; Retroviridae; Role; Site; Virulence; Virus; Work; env Genes; in vitro Model; in vivo; mathematical model; mutant; novel; pressure; receptor; response

PROJECT SUMMARY (See instmctions): Retroviruses exhibit a wealth of evolutionary phenomena, including the ability of replicating populations 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 engaged all these aspects of retrovirus evolution: We have studied the evolution of env genes by analyzing unusual mutants that extend the host range of ALV beyond chicken, to quail, dog, and even human cells. We have analyzed the evolutionary pathway as well as the novel biochemical mechanism involved. We have extensively analyzed the coevolution of retroviruses and their hosts, both in humans and in mice. We have probed the role of an important antiviral host factor (AP0BEC3G) in the evolution of both endogenous MLV and exogenous HIV. 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, and begun development of an in vitro model system to apply these models to the real world. Future work will continue these studies, with the following aims. 1. How do retroviral envelope genes evolve from receptor independence to use new receptors and to alter other important properties? 2. What are the functional and pathogenic properties of human endogenous retroviruses, particularly HERV-K? Are any of these elements still active and capable of replication and integration at new sites in the human genome? 3. How do important forces of mutation, selection, recombination, and drift combine to direct retrovirus evolution?

项目总结（见说明）： 逆转录病毒表现出丰富的进化现象，包括复制种群的能力， 在不同的选择压力下经历快速的遗传变化;在利用寄主时变化的能力 细胞受体;以及整合到其宿主物种的基因组中并传递下去的能力 作为内源性前病毒代代相传。在上一个项目期间，我们已经聘请了所有这些 逆转录病毒进化方面：我们通过分析不寻常的突变体研究了env基因的进化 将ALV的宿主范围从鸡扩展到鹌鹑、狗甚至人类细胞。我们已经分析 进化途径以及所涉及的新的生化机制。我们广泛 分析了逆转录病毒及其宿主在人类和小鼠中的共同进化。我们已经探测了 一种重要的抗病毒宿主因子（AP 0 BEC 3G）在内源性MLV和 外源性艾滋病毒。我们已经建立了复杂的数学模型来研究病毒复制的进化过程 群体，描述突变，选择，漂移，连锁和重组对 有害突变的积累（或损失），并开始开发体外模型系统以应用于 这些模型到真实的世界中。今后的工作将继续进行这些研究，目标如下。1.怎么 逆转录病毒包膜基因从受体独立性进化到使用新的受体并改变其他受体， 重要属性？2.人类内源性肿瘤的功能和致病特性是什么？ 逆转录病毒，特别是HERV-K？这些元素中是否有任何仍然活跃并能够复制， 整合到人类基因组的新位点上3.重要的突变，选择， 重组和漂移联合收割机来指导逆转录病毒的进化？