Warning: This is a preliminary report that has not been peer-reviewed. It should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information.

Yurkovetskiy L, Egri S, Kurhade C, Diaz-Salinas MA, Jaimes JA, Nyalile T, Xie X, Choudhary MC, Dauphin A, Li JZ, Munro JB, Shi P-Y, Shen K, Luban J

Abstract/SummarySARS-CoV-2 variants bearing complex combinations of mutations have been associated with increased transmissibility, COVID-19 severity, and immune escape. S:D614G may have facilitated emergence of such variants since they appeared after S:D614G had gone to fixation. To test this hypothesis, Spike sequences from an immunocompromised individual with prolonged infection, and from ...

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the major SARS-CoV-2 variants of concern, were reverted to the ancestral S:D614. In all cases, infectivity of the revertants was compromised. Rare SARS-CoV-2 lineages that lack S:D614G were identified and the infectivity of these was dependent upon S:Q613H or S:H655Y. Notably, Gamma and Omicron variants possess both S:D614G and S:H655Y, each of which contributed to infectivity of these variants. All three mutations, S:Q613H, S:D614G, and S:H655Y, stabilized Spike on virions, consistent with selection of these mutations by a common molecular mechanism. Among sarbecoviruses, S:Q613H, S:D614G, and S:H655Y are only detected in SARS-CoV-2, which uniquely possesses a polybasic S1/S2 cleavage site. Results of genetic and biochemical experiments here demonstrated that S:D614G and S:H655Y are likely adaptations to the cleavage site. CryoEM revealed that both mutations shift the Spike receptor binding domain towards the open conformation required for ACE2-binding and Spikes bearing either S:D614G or S:H655Y spontaneously mimic the smFRET signal that ACE2 induces in the parental molecule. Data from these orthogonal experiments demonstrate that S:D614G and S:H655Y are convergent adaptations to the polybasic S1/S2 cleavage site, which stabilize S1 on the virion in the open RBD conformation that is on-pathway for target cell fusion, and thereby act epistatically to promote the fitness of variants bearing complex combinations of clinically significant mutations.O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC=FIGDIR/small/535005v1_ufig1.gif ALT=Figure 1>View larger version (50K):org.highwire.dtl.DTLVardef@1dd03deorg.highwire.dtl.DTLVardef@1291a1eorg.highwire.dtl.DTLVardef@171bebborg.highwire.dtl.DTLVardef@a11b05_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIS:D614G is ubiquitous among SARS-CoV-2 B-lineage Spikes and is required for infectivity of the main Variants of ConcernC_LIO_LIIn an example of convergent evolution, rare SARS-CoV-2 A lineage viruses maintained transmission chains in the absence of S:D614G, but were instead dependent upon S:Q613H or S:H655YC_LIO_LIS:D614G and S:H655Y are both adaptations to the polybasic S1/S2 cleavage siteC_LIO_LIIncreased infectivity of S:D614G and S:H655Y is associated with a more open RBD conformation and increased steady-state levels of virion-associated S1C_LI

Date: Mar. 31, 2023

Status: Preliminary Report

View Source: doi: 10.1101/2023.03.30.535005

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