[Preprint] SARS-CoV-2 Omicron subvariants evolved to promote further escape from MHC-I recognition, Iwasaki et al

[SNT Gatchaman]

SARS-CoV-2 Omicron subvariants evolved to promote further escape from MHC-I recognition
Miyu Moriyama, Carolina Lucas, Valter Silva Monteiro, Yale SARS-CoV-2 Genomic Surveillance Initiative, Akiko Iwasaki

SARS-CoV-2 variants of concern (VOCs) possess mutations that confer resistance to neutralizing antibodies within the Spike protein and are associated with breakthrough infection and reinfection. By contrast, less is known about the escape from CD8+ T cell-mediated immunity by VOC.

Here, we demonstrated that all SARS-CoV-2 VOCs possess the ability to suppress MHC I expression. We identified several viral genes that contribute to the suppression of MHC I expression. Notably, MHC-I upregulation was strongly inhibited after SARS-CoV-2 infection in vivo. While earlier VOCs possess similar capacity as the ancestral strain to suppress MHC I, Omicron subvariants exhibit a greater ability to suppress surface MHC-I expressions.

Collectively, our data suggest that, in addition to escape from neutralizing antibodies, the success of Omicron subvariants to cause breakthrough infection and reinfection may in part be due to its optimized evasion from T cell recognition.

Significance Numerous pathogenic viruses have developed strategies to evade host CD8+ T cell-mediated clearance. Here, we demonstrated that SARS-CoV-2 encodes multiple viral factors that can modulate MHC-I expression in the host cells. We found that MHC-I upregulation was strongly suppressed during SARS-CoV-2 infection in vivo. Notably, the Omicron subvariants showed an enhanced ability to suppress MHC-I compared to the original strain and the earlier SARS-CoV-2 variants of concern (VOCs).

Our results point to the inherently strong ability of SARS-CoV-2 to hinder MHC-I expression and demonstrated that Omicron subvariants have evolved an even more optimized capacity to evade CD8 T cell recognition.

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[SNT Gatchaman]

In the current study, we uncovered the intrinsically potent ability of SARS-CoV-2 to shut down the host MHC-I system by using live, authentic SARS-CoV-2 variants as well as the functional analysis of variant-specific mutations in ORF8 gene, a key viral protein for both MHC-I evasion and adaptation to the host. We further identified multiple other viral genes that confer redundant function in MHC I suppression.

Collectively, our data shed light on the intrinsically potent ability of SARS-CoV-2 to avoid the MHC-I mediated antigen presentation to CD8+ T cells. Importantly, we observed a complete inhibition of MHC-I upregulation in lung epithelial cells infected with SARS-CoV-2 at the early stage of infection in a mouse model. Since the ability of ORF8 to downregulate MHC-I is a newly acquired feature in SARS-CoV-2 ORF8 and is absent in SARS-CoV ORF8, it is possible that ORF8 played a role in the efficient replication and transmission of SARS-CoV-2 in human and contributed to its pandemic potential.