Reply to Qu et al., “Quasispecies are constantly selected through virus-encoded intracellular reproductive population bottlenecking”

We appreciate the careful reading by F. Qu, K. Khemsom, C. Perdoncini Carvalho, and J. Han of our minireview on SARS-CoV-2 quasispecies recently published in the Journal of Virology (1). Qu and colleagues disagree with one of our assertions about viral quasispecies in general, namely that the mutant genome copies generated during viral RNA replication can collectively engage in evolution. Their main argument is that when a viral population enters a cell, it becomes strongly bottlenecked, and only one or a few of the viruses have a chance to replicate. The remaining copies are degraded, although they may contribute to the cellular modifications required for the formation of replication organelles. An advantage of such bottlenecking for virus survival is that genomes that, during prior replication, mutated to encode a different phenotype find an unchallenged cellular environment to feely multiply and express the deviant phenotype. This model is termed “Bottleneck, Isolate, Amplify, Select” (BIAS), and it is presented as contrary to the premise of quasispecies theory because “the BIAS model is unapologetically deterministic and predicts natural selection as the primary driver of virus evolution.”