Emerging SARS-CoV-2 mutations L452R & Y453F evade cellular immunity

The coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to spread globally, with the total number of cases reaching over 191 million. To date, the pandemic has claimed over 4.12 million lives.

Despite vaccination efforts, many SARS-CoV-2 variants with naturally acquired mutations have emerged. The mutations affect viral properties such as transmissibility, infectivity, and evasion of immune responses.

Researchers at the Kumamoto University and Weizmann Institute of Science found that the L452R mutation of the SARS-CoV-2 spike protein, which is common to two mutant strains, the Epsilon and Delta, can evade cellular immunity through the human leukocyte (HLA) A24 and can increase viral infectivity.

The study, published in the journal Cell Host & Microbe, also showed emerging mutations L452R and Y453F in the SARS-CoV-2 spike receptor-binding motif evade (HLA) A24-restricted cellular immunity. Meanwhile, the L452R enhances spike stability, viral fusogenicity, and viral infectivity. Hence, the findings suggest that HLA-restricted cellular immunity potentially affects the evolution of viral phenotypes.

SARS-CoV-2 mutants

Though vaccination efforts have commenced in most countries and over 3.71 billion doses have already been administered, the threat of COVID-19 is far from over. This is because emerging variants of concern (VOC) may escape immune responses induced by vaccination or natural infection.

The first reported and well-studied mutant contains a D614G substitution in the spike (S) protein. Recent studies have shown that the D614G mutation enhances the binding affinity of SARS-CoV-2 to the angiotensin-converting enzyme 2 (ACE2) receptor, the viral cellular pathway. It is also more infectious and easily transmissible. However, there is no evidence suggesting that the D614G variant is tied to increased lethality.

In the last quarter of 2020, new variants emerged – the B.1.1.7, the B.1.351, and the P.1 variants reported in the United Kingdom, South Africa, and Brazil, respectively. At the end of 2020, another lineage, the B.1.427 also called the CAL.20C, occurred in California, United States.

Currently, the world is grappling with the Delta variant (B.1.617.2), which emerged in India. Delta has been linked to increased infectivity, transmissibility, severe illness, and even death.

Interestingly, mutated viruses are mainly due to error-prone viral replication, and the spread of emerged variants is associated with the escape from immune responses. Various SARS-CoV-2 mutants may resist neutralizing mediated antibodies from COVID-19 patients and those who have received full doses of COVID-19 vaccines.

Further, the new emerging variants may escape another protection system against pathogens called the cellular immunity caused by cytotoxic T lymphocytes (CTLs). These recognize non-self epitopes present on virus-infected cells through the HLA class I molecules. This is called CTL-mediated antiviral immunity.

Recent evidence showed that human CTLs could recognize HLA-restricted SARS-CoV-2-derived epitopes. Also, the functionality of virus-specific cellular immunity correlates inversely with COVID-19 severity. Thus, CTLs play pivotal roles in controlling SARS-CoV-2 infection.

The study

The team explored the potential emergence of SARS-CoV-2 mutants that can evade HLA-restricted cellular immunity in the current study.

To arrive at the study findings, the team used immunological experiments to show that an antigen obtained from the SARS-CoV-2 spike protein is strongly recognized by the HLA-A24-restricted cellular immunity, which is often seen in Japanese people.

The team also conducted a large-scale sequence analysis of SARS-CoV-2 strains and demonstrated that HLA-A24 could recognize mutations in the spike protein region.

The team found that at least two naturally occurring substitutions in the receptor-binding motif of the SARS-CoV-2 spike protein, the L452R and Y453F identified in the B.1.427 and B1.1.298, can be resistant to the HLA-A24 cellular immunity.

The mutants also increase the virus’s binding affinity for ACE2. Experiments using pseudoviruses demonstrate that the L452R substation also enhances viral infectivity. Specifically, the L452R mutation increases the stability of the S protein, thereby enhances viral replication.

“These data suggest that HLA-restricted cellular immunity potentially affects the evolution of viral phenotypes and that a further threat of the SARS-CoV-2 pandemic is its ability to escape cellular immunity,” the team concluded in the study.

Lastly, the L452R mutation should be investigated further since the latest variant of concern, the B.1.617 lineage or the Delta variant, has caused widespread surging cases in India and other countries. Notably, the L452R mutation is a hallmark of this variant.

Journal reference:
Angela Betsaida B. Laguipo

Written by

Angela Betsaida B. Laguipo

Angela is a nurse by profession and a writer by heart. She graduated with honors (Cum Laude) for her Bachelor of Nursing degree at the University of Baguio, Philippines. She is currently completing her Master's Degree where she specialized in Maternal and Child Nursing and worked as a clinical instructor and educator in the School of Nursing at the University of Baguio.


Please use one of the following formats to cite this article in your essay, paper or report:

  • APA

    Laguipo, Angela. (2021, July 22). Emerging SARS-CoV-2 mutations L452R & Y453F evade cellular immunity. News-Medical. Retrieved on June 21, 2024 from https://www.news-medical.net/news/20210722/Emerging-SARS-CoV-2-mutations-L452R-Y453F-evade-cellular-immunity.aspx.

  • MLA

    Laguipo, Angela. "Emerging SARS-CoV-2 mutations L452R & Y453F evade cellular immunity". News-Medical. 21 June 2024. <https://www.news-medical.net/news/20210722/Emerging-SARS-CoV-2-mutations-L452R-Y453F-evade-cellular-immunity.aspx>.

  • Chicago

    Laguipo, Angela. "Emerging SARS-CoV-2 mutations L452R & Y453F evade cellular immunity". News-Medical. https://www.news-medical.net/news/20210722/Emerging-SARS-CoV-2-mutations-L452R-Y453F-evade-cellular-immunity.aspx. (accessed June 21, 2024).

  • Harvard

    Laguipo, Angela. 2021. Emerging SARS-CoV-2 mutations L452R & Y453F evade cellular immunity. News-Medical, viewed 21 June 2024, https://www.news-medical.net/news/20210722/Emerging-SARS-CoV-2-mutations-L452R-Y453F-evade-cellular-immunity.aspx.


The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
Post a new comment

While we only use edited and approved content for Azthena answers, it may on occasions provide incorrect responses. Please confirm any data provided with the related suppliers or authors. We do not provide medical advice, if you search for medical information you must always consult a medical professional before acting on any information provided.

Your questions, but not your email details will be shared with OpenAI and retained for 30 days in accordance with their privacy principles.

Please do not ask questions that use sensitive or confidential information.

Read the full Terms & Conditions.

You might also like...
AVAnT1A study: Investigating early COVID-19 vaccination and type 1 diabetes risk in children