Retrovirus Evolution

逆转录病毒表现出丰富的进化现象，包括进行快速遗传转化的能力。 响应于不同选择压力的变化;在宿主细胞受体的使用中变化的能力;以及 整合到宿主物种的基因组中并代代相传的能力 作为内源性前病毒。在前一个项目期间，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。我们已经分离出 研究了一种不寻常的小鼠内源性前病毒，它似乎占据了一个特殊的系统发育位置 小鼠和非小鼠物种之间的差异。我们广泛地分析了人类的共同进化， 它们的内源性前病毒，特别是相对最近插入的HERV-K家族。我们已经开发 复杂的数学模型的进化复制病毒种群，描述的影响， 突变、选择、漂移、连锁和重组对有害突变的积累（或损失）的影响。 今后的工作将致力于实现以下目标。1.逆转录病毒包膜基因如何进化以使用新的 受体并改变其他重要特性？我们将用我们的扩展宿主范围突变体来测试 对这一过程的具体假设。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？是他们的表情还是 与恶性肿瘤相关的再融合？3.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？我们将联合收割机结合数学和体外 病毒复制模型，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 对公众健康的重要影响。在最近的历史中，几种逆转录病毒已经进化到使用 人类作为宿主，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，增加毒力或对 毒品了解这种进化在我们过去是如何发生的，以及它是如何在简单的 模型将使我们更好地准备应对这些事件的发生。

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.