Retrovirus Evolution

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。 对不同选择压力的反应变化；宿主细胞受体使用的不同能力；以及 能够整合到寄主物种的基因组中并代代相传 作为内源性前病毒。在之前的项目期间，我们已经研究了逆转录病毒的所有这些方面 进化：我们通过分析一个不寻常的突变体，研究了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。我们已经隔离了 研究了一种不同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 在老鼠和非老鼠物种之间。我们已经广泛地分析了人类和 他们的内源性前病毒，特别是最近插入的HERV-K家族。我们已经开发出 用于复制病毒种群进化的复杂数学模型，描述了 突变、选择、漂移、连锁和重组对有害突变的积累(或丢失)。 今后的工作将着眼于以下目标。1.逆转录病毒包膜基因如何进化以使用新的 并改变其他重要的特性？我们将使用我们的扩展宿主范围突变体来测试 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，尤其是HERV-K？我们能分离出传染性病毒吗？是他们的表情还是 重新融合与恶性肿瘤有关？3.突变、选择、 重组和漂移结合起来引导逆转录病毒进化吗？我们将把数学和体外实验结合起来 对病毒复制进行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成使用 人类作为东道主，带来了毁灭性的后果。此外，给定主机内的病毒进化可以 有重要的后果，如使用不同的受体，增加毒力，或抗药性 毒品。理解这种进化在我们的过去是如何发生的，以及它是如何简单地发生的 模型将使我们在此类事件发生时做好更好的准备。

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.