key: cord-0924448-kqrqjvjg
authors: Badley, Andrew D.
title: The Yin and Yang of SARS-CoV2 Mutation and Evolution
date: 2021-02-03
journal: Mayo Clin Proc
DOI: 10.1016/j.mayocp.2021.01.023
sha: 1e6d51ca45f917653bc1fd0daf8a59afe452421a
doc_id: 924448
cord_uid: kqrqjvjg

nan

ADB is supported by grants from NIAID (grants AI110173 and AI120698) Amfar (#109593) and Mayo Clinic ( HH Shieck Khalifa Bib Zayed Al-Nahyan Named Professorship of Infectious Diseases). ADB is a paid consultant for Abbvie and Flambeau Diagnostics, is a paid member of the DSMB for Corvus Pharmaceuticals and Equilium, owns equity for scientific advisory work in Zentalis and Nference, and is founder and President of Splissen therapeutics.

RNA viruses, including the SARS-CoV2 virus, are subject to mutation because of error prone replication machinery, allowing for potential massive diversity of viral quasispecies. Multiplied by > 85 million cases suggests that virtually every possible mutation has, or will, eventually be seen. While "viral mutation" invokes cataclysmic visions of disease even worse than current, reality lies in the principles of viral population evolution, shaped by natural selection, with mutations that are beneficial to the virus being positively selected over time and those that are lethal or deleterious being removed from the population.

The life cycle of any virus involves attachment, penetration, uncoating, replication, assembly, and release. As with all biologic processes, each step requires high affinity protein:protein and protein:RNA interactions. Mutation of any of the proteins can impact the efficiency and kinetics of these interactions, which is then reflected by impaired or enhanced replicative fitness, or the ability of the virus to make more of itself. These mutations can also impact the J o u r n a l P r e -p r o o f susceptibility of viral varients to antiviral agents such as Remdesivir, or therapeutic neutralizing antibodies. Therefore when evaluating the impact of given viral mutation(s) on human disease, it is essentiual to interpret mutations in terms of replicative fitness, as well as impact on drug and antibody therapeutic efficacy ( Figure) .

One important SARS-CoV2 viral mutation is the Spike protein aspartic acid to glycine substitution at position 614 (D614G). Using in vitro infection models, and animal models of disease, this variant is associated with enhanced competitive fitness in human cells and it transmits faster than wild-type virus. 1 Consequently, the D614G isolate has became a dominant clinical strain with up to 70% of clinical isolates containing the signature mutation. 2 It is important to consider the impact of SARS-CoV2 mutations, not only in terms of viral fitness, but also with regard to susceptibility to antibody neutrailzation-of clear import for antibody based therapies, and vaccine protection. A recent study has evaluated the relationship between viral fitness, and antibody neutralization, of a diverse panel of SARS-CoV2 mutants. 3 An important finding from this paper is that SARS-CoV2 isolates containing the D614G mutation are equally inhibited by convalescent plasma as wild-type strains, 3 a finding that has since been reproduced. 1 More recently, attention has focused on SARS-CoV2 strains B.1.1.7 which is now the dominant viral quasispecies in the United Kingdom, 4 with 98% of viral isolates containing the signature mutations, 5 and B.1.351 isolated first in South Africa, and both of which appears to have enhanced spread. 4 Each virus contains multiple mutations, but they share the N501Y mutation in the receptor binding domain, which thankfully maintains susceptability to neutralizing monoclonal antibodies in vitro. 6 Reassuringly, of the 106 different mutations that they tested, only 10 variants had decreased sensitivity to convalescent plasma or neutralizing antibodies, and only one (D614G plus I472V) exhibited the worrisome combination of both enhanced replicative fitness and decreased susceptibility to antibody neutralization. 3 Separately, a study of SARS-CoV2 escape from therapeutic monoclonal antibodies identified three varients which escaped Bamlanivimab, yet one mutant (E406W) which escaped the dual antibody therapy of Casivirimab and Imdevimab 7 further supporting the contention that antibody escape is likely a rare event. The replicative fitness those varients not yet been determined.

What about the possibility of selecting for Remdesivir resistance, since treating viral infections with a single antiviral agent will often select for drug resistant J o u r n a l P r e -p r o o f variants? Serial passaging of Ebola infected cultures under pressure with Remdesivir results in an F548S substitution which confers resistance to Remdesivir, 8 and similar experiments in SARS-CoV1 infected cultures selects mutations F476L and V553L, which when engineered into MERS-CoV, confers Remdesivir resistance as well. 9 This very concerning result is tempered by observations that F480L and V557L SARS-CoV1 varients have reduced viral fitness in cell culture, and attenuated SARS-CoV1 pathogenesis in a mouse model, altogether indicating that the evolutionary cost of Remdesivir resistance is a less pathogenic virus. 9 Consistent with those observations, a recent survey of >90,000 circulating human SARS-CoV2 isolates identified mutations associated with Remdesivir resistance in only 2 cases (0.002%). 10 The most effective way to both control the SARS-CoV2 pandemic and to limit the limit the emergence of viral varients is to either prevent infection ( eg with vaccines and public health interventions) and to diagnose early and treat those who become infected with agents which block the viral lifecycle ( eg Antibody based approach or antiviral agents). Our current understanding of SARS-CoV2 mutation, evolution, and the interrelated attributes of fitness, spread, and susceptibility to antibody neutralization/antivirals, altogether suggests that when antibody or antiviral escape mutants arise, most often they do so at a cost to replicative fitness. Currently, it appears that the virus is spreading faster than it evolves. However, one must temper this observation with the fact that 13 months represents a relatively short time in evolutionary terms. It is possible that if the pandemic persists for a much longer period, we may begin to see additional adaptive mutations that limit the efficacy of available therapies.

Cell entry of SARS-CoV-2 occurs through the interaction of the receptor binding domain of Spike protein with angiotensin-converting enzyme 2 (ACE2) receptor, which causes cleavage/activation of the spike protein by cellular proteases. After fusion of the viral envelope with the cellular membrane, the viral positive strand RNA is translated into a polyprotein, and cleaved by viral proteases, forming the replicase-transcriptase complex (RTC) within doublemembrane vesicles. The RTC which contains error prone RNA dependent RNA polymerase, then mediates viral RNA replication, which in turn leads to viral protein synthesis and to production of more viral RNA. Viral proteins translocate to the endoplasmic reticulum (ER), where they assemble in the ER-Golgi intermediate compartment (ERGIC), and daughter virions are released by exocytosis. These daughter virions often contain mutations due to the error prone nature of the replication cycle, and these mutants may alter different aspects of COVID-19 pathophysiology, which can be good (Green), bad (Red), or indifferent (Yellow) to the human host.

SARS-CoV-2 D614G variant exhibits efficient replication ex vivo and transmission in vivo

SARS-CoV-2 spike-protein D614G mutation increases virion spike density and infectivity

The Impact of Mutations in SARS-CoV-2 Spike on Viral Infectivity and Antigenicity

Emerging SARS-CoV-2 Variants

Transmission of SARS-CoV-2 Lineage B.1.1.7 in England: Insights from linking epidemiological and genetic data

Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants

Prospective mapping of viral mutations that escape antibodies used to treat

Remdesivir targets a structurally analogous region of the Ebola virus and SARS-CoV-2 polymerases

Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease

Genetic Conservation of SARS-CoV-2 RNA Replication Complex in Globally Circulating Isolates from Humans and Minks Predicts Minimal Pre-Existing Resistance to Remdesivir