Retrovirus Evolution

描述(申请人提供)：逆转录病毒表现出丰富的进化现象，包括在不同的选择压力下经历快速基因变化的能力；在宿主细胞受体的使用上发生变化的能力；以及整合到宿主物种的基因组中并作为内源性前病毒代代相传的能力。在之前的项目期间，我们已经研究了逆转录病毒进化的所有这些方面：我们通过分析一个不寻常的突变体来研究env基因的进化机制，该突变体将ALV的宿主范围从鸡扩展到鹌鹑、狗，甚至人类细胞。我们分离并研究了一种不寻常的小鼠内源性前病毒，它似乎在小鼠和非小鼠物种之间占据了一个特殊的系统发育位置。我们已经广泛地分析了人类及其内源性前病毒的共同进化，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，描述了突变、选择、漂移、连锁和重组对有害突变积累(或丢失)的影响。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来测试这一过程的特定假设。2.人类内源性逆转录病毒，特别是HERV-K的功能和致病特性是什么？我们能分离出传染性病毒吗？它们的表达或重新整合是否与恶性肿瘤有关？3.突变、选择、重组和漂移的力量如何结合在一起指导逆转录病毒的进化？我们将结合病毒复制的数学模型和体外模型来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，逆转录病毒的进化对公共卫生也有重要的影响。在近代史上，几种逆转录病毒已经进化成以人类为宿主，造成了毁灭性的后果。此外，病毒在特定宿主内的进化可能会产生重要的后果，例如使用不同的受体、增加毒力或抗药性。理解这种进化是如何在我们的过去发生的，以及它是如何在简单的模型中发生的，将使我们更好地准备好在发生此类事件时处理它们。

DESCRIPTION (provided by applicant): 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 modeling 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.