Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can mutate to affect the management of COVID-19, from diagnosis to developing antivirals and vaccines. As part of natural selection, SARS-CoV-2 undergoes mutations in adjustment to its environment. The speed with which the COVID-19 infection spreads raises questions about whether the evolution of SARS-CoV-2 occurred due to viral mutations.

SARS-CoV-2 is an RNA virus known to have a high mutation rate compared to DNA viruses. SARS-CoV-2 mutations can cause different variations of the virus in different parts of the world regarding the pathogenesis and virulence of COVID-19. An understanding of the mutations and variations of SARS-CoV-2 is needed in predicting transmission of viral infections, immune protection against re-infection, and developing antivirals and vaccines against COVID-19.

The viral mutation is a method of adapting viruses to their environment. Viral mutation rates differ based on the type of virus. The mutation rate is the probability that a change in genetic information will be passed on to the next viral generation. RNA viruses (single-stranded viruses) have a higher mutation rate than DNA viruses (double-stranded viruses), and genome size negatively affects the mutation rate. RNA viruses, such as SARS, influenza, Ebola, hepatitis C, and retroviruses, can rapidly change the genome as a means of adapting to their host, avoiding immunity due to vaccination, and developing resistance to medicaments.


Studies regarding SARS-Cov-2 Mutations 

SARS-CoV-2 is a single-stranded RNA virus with open reading frames (ORFs) with positive polarity and variables. About two-thirds of the viral genome is at the first ORF, translating to the polyproteins PP1a and pp1ab. These two polyproteins encode 16 non-structural proteins (NSPs). The remaining one-third of the SARS-CoV-2 virus genome encodes structural proteins, including nucleocapsid proteins (N), spike glycoproteins (S), matrix proteins (M), and small envelope proteins (E). Of the four structural proteins, the S protein has an important role in the attachment and entry of viruses into the host cell.

Mutations in protein S are a big factor in the pathogenesis of COVID-19 because mutations in protein S can change viral tropism, including viral adaptation to their host and viral pathogenesis, so understanding SARS-CoV-2 S protein mutations in various parts of the world play an important role in the understanding transmission of this virus.

Abdullahi et al. conducted a review of various studies examining the SARS-CoV-2 mutation. In this review, they found that mutations occurred in different regions around the world. These mutations differ in SARS-CoV-2 glycoprotein S, among which they have different single nucleotide variants (SNVs) than those found in the Chinese study.

These mutations are associated with variations in the pathogenesis of SARS-CoV-2. In another study in Italy, Mutations in NSP2 and NSP3 affecting differences in virulence and pathogenesis between SARS-CoV-2 and SARS-CoV-1. Other NSP mutations, such as NSP6, NSP11, NSP13, and glycoprotein S, were found in England studies. In America and Nigeria, mutations were found in D614G in protein S, where this mutation is thought to increase transmission and evasion in the immune system. Other studies discussed in this review found that SARS-CoV-2 mutations occurred predominantly in NSP, glycoprotein S, and RNA-dependent RNA polymerase (RdRp).

Pachetti et al. also analyzed 220 SARS-CoV-2 genomes recorded in the Global Initiative on Sharing All Influenza Data (GISAID) database. This study divides data into 4 geographic areas: Asia, Oceania, Europe, and North America. In addition to finding mutations that have been previously reported, this study also found eight novel mutations of SARS-CoV-2. This study also found differences in total mutation rates in the four geographic areas, with North America with the highest total mutation rates, followed by Europe, Oceania, and Asia.

There are differences in mutation rates based on the genomic data period. In January 2020, the highest mutation rate was in Asia, while in March 2020, the highest mutation rates were found in Europe and North America. The study also found mutations in RdRp in genomic data in England and Italy that were not previously reported. This indicates the virus's development and the possible presence of different strains of SARS-CoV-2 in Europe, Asia, and North America.


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Effects of Virus Mutation in Management of COVID-19

Viral mutations can impact the management of COVID-19, from diagnosis, management to vaccine development. Due to its high mutation rate as a single-stranded RNA virus, careful understanding and monitoring of SARS-CoV-2 mutations and variations are necessary.

Osório et al. performed an analysis of 1825 SARS-CoV-2 genomic data recorded in the GISAID database. The study compared SARS-CoV-2 genomic data with Wuhan-Hu-1 data as viral genomic data obtained from pneumonia virus isolates on the market in Wuhan, China, and analyzed the suitability of binding sites on 33 oligonucleotides used by various centers and the World Health Organization ( WHO) for RT-qPCR detection of SARS-CoV-2 in human samples.

The analysis conducted found mutations of at least one genome in 79% (26 of 33) of the binding sites used for RT-qPCR assays. Also, three nucleotide substitutions (GGG substituted into AAC) were found at the beginning of the binding site in 14% of the genomes isolated from 24 different countries. This suggests that RT-qPCR may be ineffective in detecting up to 14% of the SARS-CoV-2 variation.

Effect of SARS-CoV-2 Mutations on Medical COVID-19

In the previously discussed study by Pachetti et al., the analysis found mutations in the RdRp gene in genomic data in England and Italy. A review conducted by Abdullahi et al. found various studies that found an RdRp mutation in the SARS-CoV-2 genome.

Mutations in the RdRp gene can interfere with the development of medical management of COVID-19, especially some polymerase inhibitors currently in clinical trials, such as favipiravir, galidesivir, remdesivir, ribavirin, penciclovir, galidesivir, and ponatinib. Other drugs, such as simeprevir, filibuvir, and tegobuvir, also work by binding to RdRp. RdRp mutations can lead to decreased drug efficacy and increased drug resistance. The high mutation of the RdRp gene for SARS-CoV-2 suggests the need for further studies on the effect of the RdRp mutation on antiviral drugs.

Effect of SARS-CoV-2 Mutations on COVID-19 Vaccine Development

In addition to its effect on RT-qPCR and medical management, mutations in SARS-CoV-2 can affect vaccine development to prevent the spread of COVID-19. SARS-CoV-2 enters cells through glycoprotein S bonds with the host angiotensin-converting enzyme 2 (ACE2) receptor, so the development of the COVID-19 vaccine is carried out by targeting glycoprotein S as antibody-mediated neutralization.

However, in a review conducted by Abdullahi et al., glycoprotein S is one of the locations for the most SARS-CoV-2 mutations. Also, the analysis conducted by Phelan et al. On 5,349 SARS-CoV-2 genomic data, obtained 512 mutations of glycoprotein S. This analysis shows that glycoprotein S mutations can affect vaccines' efficacy because vaccines' entry into the host body will increase the selection process and can force viruses to experience mutations with a higher frequency.




Summary
SARS-CoV-2 is a single-stranded RNA virus that is known to have a high mutation rate. The SARS-CoV-2 mutations that have been recorded in several studies have been found in NSP, glycoprotein S, and RdRp. Mutations that have occurred can hinder the management of COVID-19, such as diagnosis with RT-qPCR, medical management, to vaccine development.

The mutation of the binding site oligonucleotide can reduce the effectiveness of RT-qPCR in the detection of various SARS-CoV-2 variations. Mutations in the RdRp gene may interfere with the development and efficacy of COVID-19 antiviral medicaments. The glycoprotein S mutation could influence the development of the COVID-19 vaccine. Mutations and variations of SARS-CoV-2 are important factors that need to be considered in the development of COVID-19 management.


References
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