SARS-CoV-2 spike L452R variant evades cellular immunity and increases infectivity
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Abstract
Many SARS-CoV-2 variants with naturally acquired mutations have emerged. These mutations can affect viral properties such as infectivity and immune resistance. Although the sensitivity of naturally occurring SARS-CoV-2 variants to humoral immunity has been investigated, sensitivity to human leukocyte antigen (HLA)-restricted cellular immunity remains largely unexplored. Here, we demonstrate that two recently emerging mutations in the receptor-binding domain of the SARS-CoV-2 spike protein, L452R (in B.1.427/429 and B.1.617) and Y453F (in B.1.1.298), confer escape from HLA-A24-restricted cellular immunity. These mutations reinforce affinity toward the host entry receptor ACE2. Notably, the L452R mutation increases spike stability, viral infectivity, viral fusogenicity, and thereby promotes 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 escape from cellular immunity.
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The L452R mutation has been associated with an increased affinity for receptor binding with a resultant increased in vitro infectivity.
“The L452R mutation has been associated with an increased affinity for receptor binding with a resultant increased in vitro infectivity8.”
From Emergence of SARS-CoV-2 Omicron lineages BA.4 and BA.5 in South Africa (2022) · cites this paper as [8]
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SARS-CoV-2–specific CD8+ T cell responses in convalescent COVID-19 individuals
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Increased mortality in community-tested cases of SARS-CoV-2 lineage B.1.1.7Preprint
Davies, N. G., Jarvis, C. I., CMMID COVID-19 Working Group, Edmunds, W. J., Jewell, N. P., Diaz‐Ordaz, K., & Keogh, R. H. (2021) · medRxiv · doi:10.1101/2021.02.01.21250959 · Cited by 211 · see citing works
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Torii, S., Ono, C., Suzuki, R., Morioka, Y., Anzai, I., Fauzyah, Y., Maeda, Y., Kamitani, W., Fukuhara, T., & Matsuura, Y. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109014 · Cited by 170 · see citing works
Self-citationBroad and Differential Animal Angiotensin-Converting Enzyme 2 Receptor Usage by SARS-CoV-2
Zhao, X., Chen, D., Szabla, R., Zheng, M., Li, G., Du, P., Zheng, S., Li, X., Song, C., Li, R., et al. (2020) · Journal of Virology · doi:10.1128/jvi.00940-20 · Cited by 165 · see citing works
SARS-CoV-2 and the human-animal interface: outbreaks on mink farms
Koopmans, M. (2020) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(20)30912-9 · Cited by 160 · see citing works
Bioinformatic prediction of potential T cell epitopes for SARS-Cov-2
Kiyotani, K., Toyoshima, Y., Nemoto, K., & Nakamura, Y. (2020) · Journal of Human Genetics · doi:10.1038/s10038-020-0771-5 · Cited by 145 · see citing works
Tracy: basecalling, alignment, assembly and deconvolution of sanger chromatogram trace files
Rausch, T., Fritz, M. H.-Y., Untergasser, A., & Benes, V. (2020) · BMC Genomics · doi:10.1186/s12864-020-6635-8 · Cited by 130 · see citing works
Maldonado, F., Rafael, F. J., Shinall, M. C., & Ely, E. W. (2020) · Critical Care Medicine · doi:10.1097/ccm.0000000000004475 · Cited by 112 · see citing works
Variants with the N501Y mutation extend SARS-CoV-2 host range to mice, with contact transmissionPreprint
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Directed evolution of proteins for increased stability and expression using yeast display
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SARS-CoV-2 mutations acquired in mink reduce antibody-mediated neutralization
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Robust SARS-CoV-2-specific T-cell immunity is maintained at 6 months following primary infectionPreprint
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Emergence of a novel SARS-CoV-2 strain in Southern California, USAPreprint
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Super-rapid quantitation of the production of HIV-1 harboring a luminescent peptide tag
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Zooanthroponotic potential of SARS-CoV-2 and implications of reintroduction into human populations
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Author response: Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants
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Application of the Restriction-Free (RF) Cloning for Multicomponents Assembly
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Monitoring Viral‐Mediated Membrane Fusion Using Fluorescent Reporter Methods
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HLA-B51 transgenic mice as recipients for production of polymorphic HLA-A, B-specific antibodies
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Comparative study on the effect of human BST-2/Tetherin on HIV-1 release in cells of various species
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Self-citationHu, C., Shen, M., Han, X.-J., Chen, Q., Li, L., Chen, S.-Y., Zhang, J., Gao, F.-X., Wang, W., Wang, Y.-M., et al. (2020) · bioRxiv · doi:10.1016/j.gendis.2021.05.006 · Cited by 41 · see citing works
Ikeda, T., Symeonides, M., Albin, J. S., Li, M., Thali, M., & Harris, R. S. (2018) · PLoS Pathogens · doi:10.1371/journal.ppat.1007010 · Cited by 37 · see citing works
Self-citationA Simplified Quantitative Real-Time PCR Assay for Monitoring SARS-CoV-2 Growth in Cell Culture
Mugisha, C. S., Vuong, H. R., Puray‐Chavez, M., Bailey, A. L., Fox, J. M., Chen, R. E., Wessel, A. W., Scott, J. M., Harastani, H., Boon, A. C. M., et al. (2020) · mSphere · doi:10.1128/msphere.00658-20 · Cited by 37 · see citing works
Natural APOBEC3C variants can elicit differential HIV-1 restriction activity
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Self-citationAssessing the SARS-CoV-2 threat to wildlife: Potential risk to a broad range of mammals
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Total predicted MHC-I epitope load is inversely associated with population mortality from SARS-CoV-2
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HIV-1 restriction by endogenous APOBEC3G in the myeloid cell line THP-1
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Flagged first, then by citations
Research works printed but not linked: 1
- Wang P. Nair M.S. Liu L. Iketani S. Luo Y. Guo Y. Wang M. Yu J. Zhang B. Kwong P.D. Antibody Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7 Nature 593 2021 130 135 33684923
Cited by
Sorted by citations
SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion
Mlcochova, P., Kemp, S. A., Dhar, M. S., Papa, G., Meng, B., Ferreira, I. A. T. M., Datir, R., Collier, D. A., Albecka, A., Singh, S., et al. (2021) · Nature · doi:10.1038/s41586-021-03944-y · Cited by 1,337 · see citing works
Self-citationThe biological and clinical significance of emerging SARS-CoV-2 variants
Tao, K., Tzou, P. L., Nouhin, J., Gupta, R. K., de Oliveira, T., Kosakovsky Pond, S. L., Fera, D., & Shafer, R. W. (2021) · Nature Reviews Genetics · doi:10.1038/s41576-021-00408-x · Cited by 1,009 · see citing works
Emergence of SARS-CoV-2 Omicron lineages BA.4 and BA.5 in South Africa
Tegally, H., Moir, M., Everatt, J., Giovanetti, M., Scheepers, C., Wilkinson, E., Subramoney, K., Makatini, Z., Moyo, S., Amoako, D. G., et al. (2022) · Nature Medicine · doi:10.1038/s41591-022-01911-2 · Cited by 707 · see citing works
Impact of the delta variant on vaccine efficacy and response strategies
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Chen, X., Chen, Z., Azman, A. S., Sun, R., Lu, W., Zheng, N., Zhou, J., Wu, Q., Deng, X., Zhao, Z., et al. (2022) · Clinical Infectious Diseases · doi:10.1093/cid/ciab646 · Cited by 113 · see citing works
Partial resistance of SARS-CoV-2 Delta variants to vaccine-elicited antibodies and convalescent sera
Tada, T., Zhou, H., Dcosta, B. M., Samanovic, M. I., Mulligan, M. J., & Landau, N. R. (2021) · iScience · doi:10.1016/j.isci.2021.103341 · Cited by 101 · see citing works
“Amino acid 452 does not directly contact ACE2 but is located in proximity to a negatively charged patch in ACE2 (E35, E37, and D38) (Motozono et al., 2021).”
Mlcochova, P., Kemp, S., Dhar, M. S., Papa, G., Meng, B., Mishra, S., Whittaker, C., Mellan, T., Ferreira, I., Datir, R., et al. (2021) · doi:10.1101/2021.05.08.443253 · Cited by 90 · see citing works
Self-citationMutations that adapt SARS-CoV-2 to mink or ferret do not increase fitness in the human airway
Zhou, J., Peacock, T. P., Brown, J. C., Goldhill, D. H., Elrefaey, A. M. E., Penrice-Randal, R., Cowton, V. M., De Lorenzo, G., Furnon, W., Harvey, W. T., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110344 · Cited by 64 · see citing works
Shooting at a Moving Target—Effectiveness and Emerging Challenges for SARS-CoV-2 Vaccine Development
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- Authors
- Motozono, C., Toyoda, M., Zahradnik, J., Saito, A., Nasser, H., Tan, T. S., Ngare, I., Kimura, I., Uriu, K., Kosugi, Y., Yue, Y., Shimizu, R., Ito, J., Torii, S., Yonekawa, A., Shimono, N., Nagasaki, Y., Minami, R., Toya, T., Sekiya, N., Fukuhara, T., Matsuura, Y., Schreiber, G., Ikeda, T., Nakagawa, S., Ueno, T., & Sato, K.
- Affiliations
- Joint Research Center for Human Retrovirus Infection, Kumamoto University (JP)
- University of Miyazaki (JP)
- Suez Canal University (EG)
- Institute of Medical Science, The University of Tokyo (JP)
- Center for Infectious Disease Education and Research, The University of Osaka (JP)
- Kyushu University (JP)
- National Kyushu Medical Center (JP)
- Tokyo Metropolitan Komagome Hospital (JP)
- Hokkaido University (JP)
- Weizmann Institute of Science (IL)
- Tokai University (JP)
- Japan Science and Technology Agency (JP)
- Corresponding author
- Ikeda, Terumasa
- Nakagawa, So
- Ueno, Takamasa
- Sato, Kei
- ORCID
- Venue
- Cell Host & Microbe
- Publisher
- Elsevier BV
- Published
- 2021-07
- Volume
- 29
- Issue
- 7
- Pages
- 1124-1136.e11
- ISSN
- 1931-3128 (ISSN-L)
- PMC
- PMC8205251
- OpenAlex
- W3170097501
- Cited by
- 586
- References
- 111
- Citations by year
- 2026: 20 · 2025: 47 · 2024: 92 · 2023: 114 · 2022: 205 · 2021: 107
- FWCI
- 41.02
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell Host & Microbe (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- AMED
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- SARS-CoV-2, spike protein, L452R mutation, HLA-A24, receptor binding domain, viral infectivity, B.1.617, viral evolution
- MeSH terms
- Angiotensin-Converting Enzyme 2, COVID-19, SARS-CoV-2, Humans, Immunity, Cellular, Mutation, Phylogeny, Protein Binding, Viral Proteins, Virus Replication, Genome, Viral, Spike Glycoprotein, Coronavirus
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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