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Predicting the evolutionary patterns of emerging and endemic viruses is key for mitigating their spread. In particular, it is critical to rapidly identify mutations with the potential for immune escape or increased disease burden. Knowing which circulating mutations pose a concern can inform treatment or mitigation strategies such as alternative vaccines or targeted social distancing. In 2021, Hie B, Zhong ED, Berger B, Bryson B. 2021 Learning the language of viral evolution and escape.Science371, 284–288. (doi:10.1126/science.abd7331) proposed that variants of concern can be identified using two quantities extracted from protein language models, grammaticality and semantic change. These quantities are defined by analogy to concepts from natural language processing. Grammaticality is intended to be a measure of whether a variant viral protein is viable, and semantic change is intended to be a measure of potential for immune escape. Here, we systematically test this hypothesis, taking advantage of several high-throughput datasets that have become available, and also comparing this model with several more recently published machine learning models. We find that grammaticality can be a measure of protein viability, though methods that are trained explicitly to predict mutational effects appear to be more effective. By contrast, we do not find compelling evidence that semantic change is a useful tool for identifying immune escape mutations. 

Abstract RNA viruses have high mutation rates, with the majority of mutations being deleterious. We examine patterns of deleterious mutation accumulation over multiple rounds of viral replication, with a focus on how cellular coinfection and heterogeneity in viral output affect these patterns. Specifically, using agent-based intercellular simulations we find, in agreement with previous studies, that coinfection of cells by viruses relaxes the strength of purifying selection and thereby increases the rate of deleterious mutation accumulation. We further find that cellular heterogeneity in viral output exacerbates the rate of deleterious mutation accumulation, regardless of whether this heterogeneity in viral output is stochastic or is due to variation in the cellular multiplicity of infection. These results highlight the need to consider the unique life histories of viruses and their population structure to better understand observed patterns of viral evolution.