SARS-CoV-2 spike L452R variant evades cellular immunity and increases infectivity

• Published in: Cell host & microbe 2021-07, Vol.29 (7), p.1124-1136.e11
• Main Authors: Motozono, Chihiro, Toyoda, Mako, Zahradnik, Jiri, Saito, Akatsuki, Nasser, Hesham, Tan, Toong Seng, Ngare, Isaac, Kimura, Izumi, Uriu, Keiya, Kosugi, Yusuke, Yue, Yuan, Shimizu, Ryo, Ito, Jumpei, Torii, Shiho, Yonekawa, Akiko, Shimono, Nobuyuki, Nagasaki, Yoji, Minami, Rumi, Toya, Takashi, Sekiya, Noritaka, Fukuhara, Takasuke, Matsuura, Yoshiharu, Schreiber, Gideon, Ikeda, Terumasa, Nakagawa, So, Ueno, Takamasa, Sato, Kei
• Format: Article
• Language: English
• Subjects: Angiotensin-Converting Enzyme 2; B.1.1.298; B.1.427/429; cellular immunity; COVID-19; COVID-19 - epidemiology; COVID-19 - virology; Genome, Viral; Humans; Immunity, Cellular; L452R; Mutation; naturally occurring variants; Phylogeny; Protein Binding; receptor-binding motif; SARS-CoV-2; SARS-CoV-2 - genetics; SARS-CoV-2 - immunology; Short; Spike Glycoprotein, Coronavirus - genetics; Spike Glycoprotein, Coronavirus - immunology; spike protein; Viral Proteins - genetics; Virus Replication; Y453F
• ISSN: 1931-3128; 1934-6069; 1934-6069
• DOI: 10.1016/j.chom.2021.06.006

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. [Display omitted] •L452R and Y453F mutations in the SARS-CoV-2 spike RBM have emerged•L452R and Y453F mutants escape HLA-A24-restricted cellular immunity•L452R increases viral infectivity and fusogenicity and promotes viral replication Motozono and G2P-Japan Consortium et al. show that the emerging mutations L452R and Y453F in the SARS-CoV-2 spike receptor-binding motif evade HLA-A24-restricted cellular immunity. L452R increases spike stability, viral infectivity, and viral fusogenicity, thereby promoting viral replication. These data suggest that HLA-restricted cellular immunity potentially affects evolution of viral phenotypes.