RT Journal Article
SR Electronic
T1 SARS-CoV-2 Spike protein variant D614G increases infectivity and retains sensitivity to antibodies that target the receptor binding domain
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.07.04.187757
DO 10.1101/2020.07.04.187757
A1 Leonid Yurkovetskiy
A1 Kristen E. Pascal
A1 Christopher Tomkins-Tinch
A1 Thomas Nyalile
A1 Yetao Wang
A1 Alina Baum
A1 William E. Diehl
A1 Ann Dauphin
A1 Claudia Carbone
A1 Kristen Veinotte
A1 Shawn B. Egri
A1 Stephen F. Schaffner
A1 Jacob E. Lemieux
A1 James Munro
A1 Pardis C. Sabeti
A1 Christos A. Kyratsous
A1 Kuang Shen
A1 Jeremy Luban
YR 2020
UL http://biorxiv.org/content/early/2020/07/04/2020.07.04.187757.abstract
AB Virus genome sequence variants that appear over the course of an outbreak can be exploited to map the trajectory of the virus from one susceptible host to another. While such variants are usually of no functional significance, in some cases they may allow the virus to transmit faster, change disease severity, or confer resistance to antiviral therapies. Since the discovery of SARS-CoV-2 as the cause of COVID-19, the virus has spread around the globe, and thousands of SARS-CoV-2 genomes have been sequenced. The rate of sequence variation among SARS-CoV-2 isolates is modest for an RNA virus but the enormous number of human-to-human transmission events has provided abundant opportunity for selection of sequence variants. Among these, the SARS-CoV-2 Spike protein variant, D614G, was not present in the presumptive common ancestor of this zoonotic virus but was first detected in late January in Germany and China. The D614G variant steadily increased in frequency and now constitutes >97% of isolates world-wide, raising the question whether D614G confers a replication advantage to SARS-CoV-2. Structural models predict that D614G would disrupt contacts between the S1 and S2 domains of the Spike protein and cause significant shifts in conformation. Using single-cycle vectors we showed that D614G is three to nine-fold more infectious than the ancestral form on human lung and colon cell lines, as well as on other human cell lines rendered permissive by ectopic expression of human ACE2 and TMPRSS2, or by ACE2 orthologues from pangolin, pig, dog, or cat. Nonetheless, monoclonal antibodies targeting the receptor binding domain of the SARS-CoV-2 Spike protein retain full neutralization potency. These results suggest that D614G was selected for increased human-to-human transmission, that it contributed to the rapidity of SARS-CoV-2 spread around the world, and that it does not confer resistance to antiviral therapies targeting the receptor binding domain.Competing Interest StatementP.C.S. is a co-founder and shareholder of Sherlock Biosciences, and a Board member and shareholder of Danaher Corporation. J.E.L. consulted for Sherlock Biosciences. C.A.K., K.E.P., and A.B. are employed by Regeneron Pharmaceuticals and own stock/options of the company. C.A.K. is an officer at Regeneron.