Yesterday, a news that “18 mutated viruses appeared in the body of a Russian female patient” blasted Weibo and Moments. Many people shouted “It’s terrible,” and some pointed out that this “explosive news” was just a rumor caused by a media compilation error.
What did this report by Russian researchers say? Is the online news true or not? Dingxiangyuan interprets these issues from the following perspectives.
This controversial news originated from a paper issued by virological.org on January 4, “Emergence of Y453F and Δ69-70HV mutations in a lymphoma patient with long-term positive lymphoma patients with new crowns.” long-term COVID-19), the author is a researcher from Moscow Skolkovo Institute of Science and Technology, First Pavlov State Medical University and other units.
Patient S, female, 47 years old, with non-Hodgkin diffuse large B-cell lymphoma stage IV, was admitted to the hospital for chemotherapy on March 27, 2020. From April 5th to April 8th, patient S underwent R-ICE regimen (ritova + ifosfamide + carboplatin + etoposide) chemotherapy.
Between April 10 and April 16, patient S had close contact with patient A. Patient A was later tested positive for the new coronavirus and died of new coronary pneumonia. On April 30, patient S was tested positive for the new coronavirus and developed symptoms of new coronavirus. After at least 17 consecutive nucleic acid tests for more than four months, patient S was positive. It was not until September 12 that the test results turned negative.
The researchers compared the sampling results of the first positive nucleic acid of patient S and the last positive nucleic acid, and placed the sequencing results in the B.1.1 virus system tree, and found that the virus in patient S produced 18 specific mutations, namely intra-host mutations ( intra-host polymorphism).
At the same time, the researchers also sequenced patient A’s samples. The researchers placed it in the B.1.1.163 lineage based on the A12886G mutation in the sample of patient S. Although this lineage is mainly composed of Russian samples, it is inconsistent with the phylogenetic location of the sample of patient A, suggesting that the virus is spreading from patient A Mutations also occurred during the journey to S patient.
It can be seen that the virus in patient SThere were only 18 mutations in the host（The lineage of patient S carries the remaining 18 genetic changes.），Rather than as the news compiled by the media, there were 18 mutant viruses.Although several ribonucleotides have been replaced or deleted, the new coronavirus is still a new coronavirus.
Image source: virological.org
How did the mutation occur?
In the 132 days from April 10 to August 20, the new coronavirus in patient S has 18 mutation sites, which is equivalent to 1.67E-3 mutations/nucleotide/year, which is significantly higher than the new coronavirus The average rate of evolution.
This is the result of impaired immune function in patients with lymphoma. The researchers counted the mutation types at each mutation site. The estimated ratio of the number of non-synonymous and synonymous substitutions was 0.99, which was higher than the average value of all external lineages in B.1.1 (mean=0.57, median=0.55). Although the difference is not significant (p=0.1).
Researchers believe that this is because the patient’s immune function is reduced, the virus has a relaxed selective constraint (relaxed selective constraint) and/or the result of positive selection (positive selection).
It is worth noting that the virus in patient S produced both “Δ69-70HV” and “Y453F” mutations (ΔF combination) at the same time. This combination of mutations was originally a specific mutation in the mink, and later passed back to humans. However, patient S has no history of exposure to mink, so the researchers believe that these two mutations were produced independently in her body.
In addition to the ΔF combination, patient S also acquired two other mutations, one is S: Δ141-144, which has previously appeared in another patient with low immune function; the other is the early termination of the translation of ORF8.
The nonsense mutation at codon 27 of ORF8 is one of the pedigree-defining mutations of mutant B.1.1.7, and it is also considered to be produced in chronically infected individuals. Since ORF8 is believed to suppress the immune response, the choice of ORF8-deficient virus may be relaxed in patients with weakened immune function.
Image source: virological.org
How to understand the meaning of 18 mutations?
Although the results of the study are not as exaggerated as those posted on the Internet, the mutation of the virus has increased the uncertainty of the epidemic.
The ΔF combination enhances the infectivity of the virus and may evade the recognition of partially neutralizing antibodies, which means that the effectiveness of the vaccine may be challenged.Fortunately, the current mutations have not affected the effectiveness of vaccines that have been developed and used.
The Y453F mutation affects the receptor binding domain (RBD) of the virus, increases the binding to hACE2, and allows the virus to have a certain degree of immune escape from some monoclonal antibodies and polyclonal serum.
Actually,Many cases of chronic infection in immunodeficiency patients have been reported(Choi B., et al. NEJM; Avanzato VA., et al. Cell, etc.), this case is not special compared to the previous case.
Although there is still no evidence that these mutations can increase the toxicity of the virus, the increase in viral infectivity and immune escape they may bring is still worthy of our vigilance.
These variants appearing in immunocompromised patients may spread to the general population at any time, thereby affecting the spread of the virus and the therapeutic effect of drugs.This means that today when the epidemic is still raging,Genomic studies and epidemiological investigations of immunodeficiency patients with new coronary pneumonia should be more concerned and more in-depth.(Gyoza: gyouza, PDs.)
Acknowledgements: This article was approved by the Chinese Academy of Sciences, Shanghai Pasteur Institute, Ph.D. in [email protected]今日吃糖、Zhu Ling, Chief Physician, Nan’an District Center for Disease Control and Prevention, ChongqingProfessional review
Ph.D. in Immunology, Shanghai Pasteur Institute, Chinese Academy of [email protected]第一次吃糖 Audit opinion:
In fact, many cases of chronic infection and prolonged shedding of the new crown of immunodeficiency patients were reported in the early stage of the new crown epidemic.[2-3]Later, there is more and more evidence that the new coronavirus has undergone adaptive evolution in the host. This adaptive evolution comes from chronic infection, immunodeficiency, and selective pressure during the treatment process. It can be seen that the advantages in the entire infection process The strains are constantly changing, and these are in line with previous knowledge.
Including previous cases on NEJM , E484K and other mutations with strong escape ability have also evolved, and infectious viruses can also be isolated in samples as long as 143 days. This also implies that patients who test positive for long-term nucleic acid may not be due to the remaining viral RNA in the body. , It may indeed carry an infectious virus.
Immunodeficiency patients are also one of the risk factors for severe new coronary pneumonia, Including HIV-infected patients, patients receiving organ transplantation, patients receiving hematopoietic stem cell transplantation, and patients receiving chemotherapy, etc. These people are at higher risk of respiratory complications and have also been confirmed in influenza virus infectionDuring the 2009 pandemic, it was also observed that patients with cancer during chemotherapy and patients who received organ transplantation had prolonged H1N1 shedding time. There were also reports of chronic infections in lymphoma patients in MERS-CoV infection.[6-7]。
This case provides a certain indication for the mutation site selected by pressure, and it also reminds us that patients with immunodeficiency should pay special attention to protecting themselves, otherwise once they are infected, they will be worse and suffer more.
Zhu Ling, Chief Physician, Nan’an District Center for Disease Control and Prevention, ChongqingAudit opinion:
“18 mutated new coronaviruses found in a woman in Russia” is actually a compilation error of the media. The original text “18 mutations detected in the new coronavirus genome” was incorrectly translated as “18 mutated new coronaviruses were found in the body”. The mutation is The basis of the evolution of RNA viruses, which means that the new coronavirus is still a new coronavirus, not a new virus, let alone 18 different viruses.
Source of the title picture: Creative
 Kunisaki KM, Janoff EN. Influenza in immunosuppressed populations: a review of infection frequency, morbidity, mortality, and vaccine responses. Lancet Infect Dis. 2009 Aug;9(8):493-504.
 Kim SH., et al. Atypical presentations of MERS-CoV infection in immunocompromised hosts. J Infect Chemother. 2017 Nov;23(11):769-773.
As of 19:00 on January 14, the main changes in various regions are as follows:
- 1 case of new coronary pneumonia detected in Nanning, Guangxi
- There are 8 medium-risk areas in Shenyang
- 3 ice cream samples from Daqiao Road in Tianjin test positive for new crown
Dingxiangyuan·Dr. Dingxiang’s “Pandemic Trends” will take you the first time to understand the changes in the epidemic. Click on the card below to view.