Post-entry, spike-dependent replication advantage of B.1.1.7 and B.1.617.2 over B.1 SARS-CoV-2 in an ACE2-deficient human lung cell line (preprint)

ABSTRACT

Epidemiological data demonstrate that B.1.1.7, and even more, B.1.617.2 SARS-CoV-2 are more transmissible and infections are associated with a higher mortality than B.1 virus infection. Intrinsic properties underlying their enhanced spread in the human population remain unknown. B.1.1.7 virus isolates displayed inferior or equivalent spread in most cell lines and primary cells compared to B.1 SARS-CoV-2, and were outcompeted by the latter. Lower infectivity and delayed entry kinetics of B.1.1.7 viruses were accompanied by inefficient proteolytic processing of spike. B.1.1.7 viruses failed to escape from neutralizing antibodies, but slightly dampened induction of innate immunity. The lung cell line NCI-H1299 supported 24- and 595-fold increased growth of B.1.1.7 and B.1.617.2 viruses, respectively, in the absence of detectable ACE2 expression and in a spike-determined fashion. Superior spread in ACE2-deficient NCI-H1299 cells suggests that variants of concern employ a distinct set of cellular cofactors that may be unavailable in standard cell culture lines.