SARS-CoV-2 V483 deletion offers evolutionary edge and increased binding affinity to ACE2 of various animal species
Nikhil Prasad Fact checked by:Thailand Medical News Team Jul 22, 2024 4 months, 4 hours, 11 minutes ago
COVID-19 News: The journey of SARS-CoV-2, the virus responsible for the global COVID-19 pandemic, has been marked by continuous evolution. Since the initial outbreak in 2019, this virus has mutated multiple times, leading to various new variants. In a recent study, scientists have discovered a notable mutation involving the deletion of residue V483 in the spike protein, which appears to confer a significant evolutionary advantage to the virus. This
COVID-19 News delves into this fascinating development and what it means for human adaptation and the virus’s host range expansion.
SARS-CoV-2 V483 deletion offers evolutionary edge and increased binding affinity to ACE2 of various animal species
The Mutation That Stands Out
In this study, researchers from the Institute of Biophysics at the Chinese Academy of Sciences-China, the Changping Laboratory-China, and the University of Cambridge-UK focused on the highly mutated Omicron variant BA.2.86, which emerged abruptly after 2022 and has been classified by the World Health Organization (WHO) as a variant under monitoring (VUM). This variant has accumulated more than 30 amino acid changes from its parental BA.2 strain. Among these changes, the deletion of residue 483 (Δ483) in the receptor binding domain (RBD) region is particularly intriguing.
This deletion is found in all the spawns of BA.2.86 including the JN.1 and all the KP variants.
Typically, deletions in the spike protein of SARS-CoV-2 variants occur in the N-terminal domain (NTD). However, the absence of residue 483, which is genetically stable and does not hinder the virus’s interaction with the ACE2 receptor, is a rare occurrence. This stability suggests that Δ483 might provide a selective advantage, as strains harboring this mutation tend to become prevalent. The researchers aimed to understand the impact of this deletion on the virus's adaptation across different hosts and its role in the ongoing pandemic.
Examining the Affinity for ACE2
To investigate the potential advantages of Δ483, the researchers conducted a series of experiments. They tested the binding affinity of wild-type (WT) SARS-CoV-2, BA.1, BA.2.75, BA.2.86, and a variant with V483 inserted back into BA.2.86 (BA.2.86-V483ins) to ACE2 receptors from various animals.
The findings revealed that ACE2 from animals like cows, goats, and cats, which have a high degree of conservation with human ACE2 (hACE2), exhibited greater compatibility for binding with SARS-CoV-2 and its variants. This affinity increased progressively from the WT to BA.2.86, mirroring trends seen with hACE2. Conversely, ACE2s with lower conservation to hACE2 showed limited compatibility, even with BA.1.
Interestingly, the insertion of V483 enhanced the binding of RBD with hACE2 but decreased the binding affinity with animal-derived ACE2 by more than 1.6-fold. The results were consistent when the researchers tested the infectivity of pseudoviruses of BA.2.86 and BA.2.86-V483ins in cells overexpressing either human, bovin
e, goat, cat, mink, or mouse ACE2. The addition of V483 increased the infectivity of cells overexpressing hACE2, while it decreased the infectivity of cells overexpressing animal ACE2.
Structural Insights into V483 Deletion
To uncover the structural basis behind these observations, the researchers utilized cryo-electron microscopy (cryo-EM) to analyze the structures of BA.2.86 spike protein in complex with bovine ACE2 and BA.2.86-V483ins RBD in complex with bovine ACE2. The detailed structural analysis showed that residue 483 on RBD does not directly participate in the interaction with the ACE2 receptor. Instead, it indirectly regulates binding through conformational changes in a loop where it is located. In the context of RBD interacting with hACE2, the loop modulates interaction through hydrophobic interactions involving specific residues.
The presence of residue V483 enhances the loop's flexibility, facilitating more effective contact between the hydrophobic residues on RBD and their counterparts on hACE2. This increased the hydrophobic interaction surface area. However, the deletion of V483 reduced the loop's flexibility, diminishing these interactions and the hydrophobic surface area. In animal ACE2, the conversion of residue 82 to a hydrophilic amino acid significantly weakened the hydrophobic interactions, thus reducing the constraints on loop mobility.
Infectivity and Immunogenicity Analysis
To determine whether the deletion of V483 could become a defining characteristic in epidemic strains, the researchers conducted infectivity tests on various human cell lines with and without V483. The results showed that strains lacking V483 displayed lower infectivity.
Additionally, the study explored the immunogenicity and immune imprinting effects of V483 by analyzing mice with different immunity backgrounds. The findings indicated that both BA.2.86 and BA.2.86-V483ins induced high levels of neutralizing antibodies against BA.2.86 sub-lineages. However, BA.2.86-V483ins showed a notable antigenic drift and higher immunogenicity compared to BA.2.86.
In mice with a hybrid immunity background, BA.2.86-V483ins elicited significantly improved neutralizing titers against all tested SARS-CoV-2 variants compared to BA.2.86. Importantly, Δ483 resulted in a substantial reduction in immunogenicity and immune imprinting, benefiting immune escape and facilitating reinfections by future variants.
Implications for Vaccine Development
The structural and functional analysis suggests several potential implications.
Firstly, the absence of V483 affects the receptor affinity and infectivity of BA.2.86 across different species, indicating species-specific adaptability. Secondly, the deletion of V483 may increase the risk of animal infections by BA.2.86. Thirdly, the loss of V483 results in reduced immunogenicity and immune imprinting while enhancing the virus's evasion capability, providing an advantage for reinfections by future variants. Finally, regarding vaccine development, the supplementation of V483 could be an optimal strategy to elicit improved neutralizing titers against BA.2.86 sub-lineages.
In conclusion, this study sheds light on the evolutionary dynamics of SARS-CoV-2, offering valuable insights into virus-host interactions and significant implications for developing therapeutic strategies targeting emerging variants. However, it's important to note that the findings are based on studies conducted on mice, and there may be slight differences when applying these findings to humans.
The study findings were published in the peer-reviewed journal: Cell Research.
https://link.springer.com/article/10.1038/s41422-024-01000-8
For the latest
COVID-19 News, keep on logging to Thailand Medical News.
Read Also:
https://www.thailandmedical.news/news/forget-about-the-kp-3-lb-1-kp-2-3-variants-the-new-sars-cov-2-kp-3-1-1-is-leading-the-current-global-covid-19-surge
https://www.thailandmedical.news/news/both-clades-of-mpox-is-possibly-mutating-but-no-one-is-willing-to-divulge-the-truth
Share
Tweet
Share
