An Emerging SARS-CoV-2 Mutant Evades Cellular Immunity and Increases Infectivity

Abstract

Many variants that naturally acquire multiple mutations have emerged during the current SARS-CoV-2 pandemic, which is devastating societies worldwide. Emerging 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 recently been investigated,  sensitivity to human leukocyte antigen (HLA)-restricted cellular immunity remains unaddressed. 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 Y453F (in B.1.298), confer escape from HLA-A24-restricted cellular immunity. These mutations reinforce the affinity toward the viral receptor ACE2; notably, the L452R mutation increases spike stability and viral infectivity and potentially promotes viral replication. Our 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.

Funding: This study was supported in part by AMED Research Program on Emerging and Re-emerging Infectious Diseases 20fk0108163 (to A.S.), 20fk0108146 (to K.S.), 19fk0108171 (to S.N. and K.S.), 20fk0108270 (to K.S.) and 20fk0108413 (to T.I., S.N. and K.S.); AMED Research Program on HIV/AIDS 20fk0410019 (to T.U. and K.S.), 20fk0410014 (to K.S.) and 21fk0410039 (to K.S.); AMED Japan Program for Infectious Diseases Research and Infrastructure 20wm0325009 (to A.S.); JST J RAPID JPMJJR2007 (to K.S.); JST SICORP (e-ASIA) JPMJSC20U1 (to K.S.); JSTCREST JPMJCR20H6 (to S.N) and JPMJCR20H4 (to K.S); JSPS KAKENHI Grant-in-Aid for Scientific Research B 18H02662 (to K.S.) and 21H02737 (to K.S.); JSPS KAKENHI Grant-in-Aid for Scientific Research on Innovative Areas 16H06429 (to S.N. and K.S.), 16K21723 (to S.N. and K.S.), 17H05823 (to S.N.), 17H05813 (to K.S.), 19H04843 (to S.N.) and 19H04826 (to K.S.); JSPS Fund for the Promotion of Joint International Research (Fostering Joint International Research) 18KK0447 (to K.S.); JSPS Core-to-Core Program JPJSCCB20190009 (to T.U.) andJPJSCCA20190008 (A. Advanced Research Networks) (to K.S.); JSPS Research Fellow DC1 19J20488 (to I.K.); JSPS Leading Initiative for Excellent Young Researchers (LEADER) (to T.I.); ONO Medical Research Foundation (to K.S.); Ichiro Kanehara Foundation (to K.S.); Lotte Foundation (to K.S.); Mochida Memorial Foundation for Medical and Pharmaceutical Research (to K.S.); Daiichi Sankyo Foundation of Life Science (to K.S.); Sumitomo Foundation (to K.S.); Uehara Foundation (to K.S.); Takeda Science Foundation (to C.M., T.I. and K.S.); The Tokyo Biochemical Research Foundation (to K.S.); Mitsubishi Foundation (to T.I.); Shin Nihon Foundation of Advanced Medical Research (to T.I.); An intramural grant from Kumamoto University COVID-19 Research Projects (AMABIE) (to C.M., T.I. and T.U.); Kumamoto University International Collaborative Research Grants (to T.U.); Intercontinental Research and Educational Platform Aiming for Eradication of HIV/AIDS (to T.I. and T.U.); 2020 Tokai University School of Medicine Research Aid (to S.N.); and Joint Usage/Research Center program of Institute for Frontier Life and Medical Sciences, Kyoto University (to K.S.). T.S.T and I.N. are the recipients of the doctoral course scholarship from Japanese Government.

Conflict of Interest: The authors declare that no competing interests exist.

Ethical Approval: All protocols involving human subjects recruited at Kyushu University Hospital, Japan, National Hospital Organization Kyushu Medical Center, Japan, and Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Japan, were reviewed and approved by the Ethics Committee for Epidemiological andGeneral Research at the Faculty of Life Science, Kumamoto University (approval numbers 2066 and 461). All human subjects provided written informed consent.

Keywords: SARS-CoV-2; COVID-19; cellular immunity; spike protein; receptor-binding motif; mink; zoonosis; naturally occurring variants; B.1.427/429; B.1.298; L452R; Y453F