Mathematical Virology: The Impact of Virus Structure and Function on Viral Evolution

由于全球变暖对世界气候的影响，社会面临着一些重大挑战。其后果之一是，在其他情况下罕见且特征不明确的病毒感染传播到世界上经济发达的地区。例如，蓝舌病病毒，在被限制在温暖气候多年后抵达英国。这对公共和动物健康构成了现有病毒和新出现病毒的威胁。抗病毒治疗设计中的一个主要问题是在初始治疗后不久出现对抗病毒药物耐药的病毒株。因此，迫切需要研究可以防止这种病毒逃逸突变体的机制，以开发具有长期作用的治疗方法。此外，病毒可以进化出跨越物种屏障的菌株，例如从动物宿主到人类宿主，如禽流感，因此能够制定预防这种情况的策略非常重要。对病毒进化的深入了解可以阐明这两个问题。特别是，我们需要更好地了解病毒在基因组进化时所面临的限制，并找到预测这种进化行为的方法。在以前的研究中，我们对病毒结构和功能的约束条件有了新的认识，我们在这里研究了它们对病毒进化的影响。如果我们能够更好地理解决定病毒进化行为的因素，我们就能够探索误导病毒进化的策略。特别是，这种分析将使我们能够量化我们先前发现的结构限制导致进化瓶颈的程度，即对应于病毒逃逸突变体无法避免的限制，以及新一代抗病毒治疗剂可以靶向的限制。此外，我们计划开发预测病毒如何对药物反应的方法，并使用它来测试不同抗病毒策略的影响。这项研究有可能导致新一代的“进化稳定”疗法，这些疗法不太容易受到逃逸突变体的影响。

Society faces a number of major challenges due to the impact of global warming on world climate. One consequence is the spread of otherwise rare and poorly characterised viral infections into economically advanced areas of the world. Examples include Bluetongue virus, which arrived in the UK after years of being restricted to much warmer climates. This poses a threat to public and animal health from both existing viruses and newly emerging ones. A major problem in the design of anti-viral therapies is the emergence of viral strains that are resistant to anti-viral drugs soon after initial treatment. Research into the mechanisms that could prevent such viral escape mutants is therefore urgently required in order to develop therapeutics with long-term action. Moreover, viruses can evolve strains that cross the species barrier, for example from an animal to a human host as in the case of bird flu, and it is important to be able to develop strategies to prevent this. Insights into virus evolution could shed light on both issues. In particular, we need to better understand the constraints that viruses face when their genomes evolve, and find ways of predicting such evolutionary behaviour. In previous research we have gained fundamentally new insights into the constraints underlying virus structure and function, and we investigate here their impact on the evolution of viruses. If we improve our understanding of the factors that determine the evolutionary behaviour of viruses, we will be able to explore strategies to misdirect viral evolution. In particular, this analysis will allow us to quantify in how far the structural constraints we have discovered earlier lead to evolutionary bottlenecks, i.e. correspond to constraints that the viral escape mutants cannot avoid, and that a new generation of anti-viral therapeutics could target. Moreover, we plan to develop methods to predict how viruses may react to a drug, and use this to test the impact of different anti-viral strategies. This research has the potential to lead to a new generation of "evolutionarily-stable" therapeutics that are less susceptible to the problem of escape mutants.