Zhang Wenhong: does d614g mutation indicate uncontrolled virus transmission and vaccine failure

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 Zhang Wenhong: does d614g mutation indicate uncontrolled virus transmission and vaccine failure


What is d614g mutation?

Because of the wide host nature and the structural characteristics of its own genome, coronavirus is prone to gene recombination and genetic diversity in the process of evolution. D614g mutation refers to the mutation of amino acid 614 (aspartic acid) to glycine (glycine) at amino acid 614 of new coronavirus, which is located in S protein (Fig. 1). D614g mutant strains often have C to T mutations in 5UTR (compared with 241 in mn908947.3 genome), 3037 C-T mutations and 14408 C-T mutations. The haplotype containing these four genetic linkage mutations has become the dominant form in the world. According to the sequencing results of new coronavirus published by gisaid database, it was found that the virus strains carrying the mutations were mainly classified into G type, GR type and GH type.

Figure 1 (image source: the left image is from the network; the right image is from Zhang L, Jackson CB, mouh, etal.TheD614GmutationintheSARS -CoV-2spikeproteinreducesS1sheddingandincreasesinfectivity[J].bioRxiv,2020.uff09

Why are we so concerned about d614g mutation?

Up to now, more than 10000 different site mutations have been found in all new coronavirus genome sequences published in gisaid database, but d614g has attracted extensive attention.

1) In terms of transmission scope, quantity and proportion: before March this year, all types of virus strains carrying this mutation were far from becoming the global mainstream, accounting for less than 10% of the published sequencing sequences of virus strains in the world. It was first discovered in Europe and then spread to North America, Oceania, South America and Asia. In March, the number soared to 60% - 70%. By the end of June, it was over 90%. As a result, the virus strains carrying this mutation have become the major genotype of transmission (Fig. 2).

Figure 2 (source: korber B, fischerwm, gnanakaran s, etal.TrackingchangesinSARS -CoV-2 Spike:evidencethatD614GincreasesinfectivityoftheCOVID-19virus [J].Cell,2020.uff1bDaniloskiZ,GuoX,SanjanaN, etal.TheD614GmutationinSARS -CoV-2Spikeincreasestransductionofmultiplehumancelltypes[J].bioRxiv,2020.uff09

2) Potential function: d614g mutation is a missense mutation (changes in amino acid mutation), and the mutation is located on spike protein (s protein) of new coronavirus (NCV) (Fig. 3). This protein is the core weapon of new coronavirus invading human cells, and is also the target of many vaccines and therapies. As a result, mutations in spinosin are more likely to attract the attention of many researchers - these mutations may change the structure, properties and activity of spindles, thus making it easier for viruses to invade human cells.

Figure 3 (images from the Internet)

Why does d614g stand out and sweep the world?

However, the d614g strain was not found in Asia until 2 months ago, but it did not spread to Asia for the first time. Is this because the mutation changes the activity of the spike protein and increases the aggressiveness and transmissibility of the virus, making it easier for the virus to invade human cells?

In subsequent articles published in the cell, we also calculated the viral load after in vitro infection experiment, and found that d614g mutant had higher viral load. In addition, several teams have found that d614g mutation has enhanced infectivity in human lung epithelial cells and hace2 cells.

However, a review article published at the same time in cell magazine pointed out that the new coronavirus with d614g mutation has indeed become the dominant viral strain in the world, and the cell experiment results supporting the d614g mutation to enhance the ability of new coronavirus to infect cells are also given. However, it is still uncertain whether d614g mutation will enhance the ability and toxicity of new coronavirus to infect people, which needs more clinical data. These tests do not consider the influence of other viruses or host proteins, and the interaction between host and pathogen to support infection and transmission.

Is the increase of g614 frequency necessarily related to the increase of transmission? not always! It may also be explained by the epidemiological contingency of the pandemic. After February, the epidemic situation in China was under control, and European cases became the mainstream in the world. In March, the majority of sars-cov-2 lineages in the United States came from Europe. Whether virus typing can be established in a region is not only related to transmission, but also to the number of times they are introduced.

Therefore, after the stability of domestic prevention and control, China should strengthen the prevention and control of imports. During the period when g614 became the majority of varieties in the world, the number of virus introduced in China, which was still dominated by d614, was declining sharply due to the control of the transmission of imported cases. Although the d614g mutation was found in the Beijing epidemic, the g614 virus lost the opportunity to expand greatly in China due to the rapid and decisive prevention and control measures. At the same time, great achievements have been made in Chinas anti epidemic work, leading to the effective control of the spread of d614 virus strain in China, and the proportion in the world is becoming smaller and smaller. There is no other competitor for the d614g mutant virus strain in Europe and America, which leads to the status of being the dominant one.

Is the new coronavirus strain carrying d614g mutation more virulent?

Korber et al. Found that patients infected with g614 mutant virus had higher viral RNA levels in covid-19 cases in the United Kingdom, but there was no difference in hospitalization results. Some scholars have proposed that d614g mutation has a strong correlation with disease mortality rates, but still stay in the statistical correlation analysis.

First of all, viral RNA load can not be used to measure the severity of the disease. High titers of virus also exist in asymptomatic infected patients, and the above analysis is related statistical analysis, without clear evidence. At the same time, current evidence suggests that d614g is less important for covid-19 than other risk factors, such as age or other underlying diseases. Therefore, the current evidence can not confirm that d614g mutation is more virulent.

Will d614g mutation affect current detection, treatment and vaccine research?

Nucleic acid detection novel coronavirus is currently recommended for open reading frame 1ab (openreadingframe, ORF1ab) and nucleoprotein (N) gene region primers and probes. According to WHO guidelines, N3 is used for universal detection of SARS like coronavirus and N1 and N2 are used for specific detection of sars-cov-2. Therefore, d614g mutation does not affect the nucleic acid detection of the virus.

The receptor binding region (RBD) of spinin is the target of many vaccines and therapies. D614g is not located in RBD region. At the same time, antibodies produced by naturally infected viruses containing d614 or g614 can be cross neutralized. Therefore, d614g mutation is unlikely to have a significant impact on the efficacy of vaccines currently being developed.

In addition, there is no evidence that d614g mutations interfere with therapeutic strategies, such as designing drugs that destroy monoclonal antibodies that bind to the spike of ACE2. However, before we can better understand the role of d614g in the natural infection of sars-cov-2, any vaccine or treatment design should consider the existence and possible impact of the mutation.

Among the new coronavirus mutations, d614g mutation virus strain stands out because of its transmission and potential function. However, the virus strain continues to mutate. At present, there is no sufficient evidence to prove the infectivity and toxicity of d614g mutant virus strain, and no significant impact on vaccine and detection has been observed. More experiments are needed to verify and monitor the mutation phenomenon in the future.

[References

1.KorberB,FischerWM,GnanakaranS, etal.TrackingchangesinSARS -CoV-2 Spike:evidencethatD614GincreasesinfectivityoftheCOVID-19virus [J].Cell,2020.

2.GrubaughND,HanageWP, RasmussenAL.Makingsenseofmutation :whatD614GmeansfortheCOVID-19pandemicremainsunclear[J].Cell,2020.

3.ZhangL,JacksonCB,MouH, etal.TheD614GmutationintheSARS -CoV-2spikeproteinreducesS1sheddingandincreasesinfectivity[J].bioRxiv,2020.

4.DaniloskiZ,GuoX,SanjanaN, etal.TheD614GmutationinSARS -CoV-2Spikeincreasestransductionofmultiplehumancelltypes[J].bioRxiv,2020.

(function(){( window.slotbydup=window .slotbydup||[]).push({id:u5811557,container:ssp_ 5811557, async:true });})();5.BecerraFloresM, CardozoT.SARS u2010CoVu20102viralspikeG614mutationexhibitshighercasefatalityrate[J].InternationalJournalofClinicalPractice, Author: Zhang Yi, Jiang Ning, Zhang Wenhong, editor: Zhang Yi, reviewer: Zhang Wenhong, author: Zhang Yi, master of infection department of Huashan Hospital, Jiang Ning, doctor of School of life science, Fudan University, Zhang Wenhong, director of infection department of Huashan Hospital. D614g mutation has occurred in Xinfadi new coronavirus in Beijing_ MN7479

5.BecerraFloresM, CardozoT.SARS u2010CoVu20102viralspikeG614mutationexhibitshighercasefatalityrate[J].InternationalJournalofClinicalPractice,2020.

Written by: Zhang Yi, Jiang Ning, Zhang Wenhong

Editor: Zhang Yi

Reviewer: Zhang Wenhong

Zhang Yi is a Postgraduates of infection department of Huashan Hospital, Jiang Ning is a doctor of Life Science College of Fudan University, and Zhang Wenhong is the director of infection department of Huashan Hospital.