Virus genomics as a clinical and epidemiological tool

In this article of EBioMedicine [1], Lorenzo-Redondo et al. use whole genome sequencing to compare the epidemiology of three SARS-CoV-2 clades that spread in Illinois during the early phase of the COVID-19 pandemic. One of these clades was defined by the now-infamous D614G substitution. Viral lineages in which the 614th amino acid of the Spike protein changed from aspartate (D) to glycine (G) now constitute the majority of SARS-CoV-2 in global circulation [2]. This study finds the correlate: a clade containing the D614 variant detected in Chicago was geographically limited in spread and was associated with lower viral loads among infected individuals. Taking this perspective, the authors consider the multi-dimensional selective forces that influence SARS-CoV-2 evolution and impact the way in which this virus interacts with our immune system. When a new viral lineage dominates the virus population to the extent that the G614 variant has, there are two likely explanations. Either the emergent variant has a fitness advantage over its predecessors or some stochastic event occurred to enable that lineage to replicate with relatively little competition. Determining which scenario applies to D614G requires that we consider the comparative fitness of the two genotypes. Biochemically, the exchange of a negatively charged amino acid (D) for a non-polar one (G) slightly modifies the configuration of the Spike protein trimer so that the receptor binding site, which interacts with the human ACE2 receptor, is more readily exposed [3,4]. Consistent with this hypothesis, a preliminary in vitro study found that pseudoviruses containing the G614 variant were more infectious in cell culture compared to their D614 counterparts [5]. Gaining entrance into host cells is the key first step in the virus replication cycle. Therefore, a virus that can latch onto a host cell receptor more easily has a competitive edge. To be sure, it is a far leap between tissue culture and a human being, but LorenzoRedondo et al. and others observe that infection with the G614 variant is associated with significantly higher viral loads in the upper respiratory tract of COVID-19 patients [1,5]. These data provide a blueprint for the bridge between the molecular and physiological,