A persistent fraction of SARS-CoV-2 virions evades antibody neutralization due to intrinsic spike heterogeneity characterized by increased furin cleavage, a closed conformation, and higher mannosidic glycan content.
SARS-CoV-2 exhibits a persistent fraction of virions with intrinsic resistance to neutralizing antibodies due to spike conformational heterogeneity.
SARS-CoV-2 Spike - the sole neutralization target, is highly resilient to the immune pressure driving genetic evolution. While potency and breadth of neutralization are widely studied, the incomplete neutralization - the mechanism of resistance without needing genetic change - remains unexplored. Several monoclonal antibodies, although potent, showed incomplete neutralization of genetically homogeneous pseudovirus suggesting the existence of distinct spike conformations. The residual infectivity at high antibody concentration indicates a viral fraction with intrinsic resistance to the antibody. Although the published studies on spike glycosylation, structure, and conformations provide evidence of spike heterogeneity the precise mechanism for the incomplete neutralization has not been established. In this study, we devise a method to separate the un-neutralized virion population, called as persistent fraction of infectivity (PF), and characterize the viral spike protein. The neutralization resistance of PF is stable and unrelated to the conformational equilibrium that exists in the pseudovirus stock. The spike on the PF is highly cleaved between S1 and S2, adopts the closed conformation, and express more mannosidic glycans on RBD than the total virus population. Our study provides possible explanations for the incomplete neutralization by antibodies and delineates the association between furin cleavage of spike, its conformation and glycosylation.
Kumar et al. (Wed,) conducted a other in SARS-CoV-2. Neutralizing antibodies was evaluated on Persistent fraction of infectivity (incomplete neutralization). A persistent fraction of SARS-CoV-2 virions evades antibody neutralization due to intrinsic spike heterogeneity characterized by increased furin cleavage, a closed conformation, and higher mannosidic glycan content.