Inhibition of major histocompatibility complex-I antigen presentation by sarbecovirus ORF7a proteins

Abstract

Viruses employ a variety of strategies to escape or counteract immune responses, including depletion of cell surface major histocompatibility complex class I (MHC-I), that would ordinarily present viral peptides to CD8 + cytotoxic T cells. As part of a screen to elucidate biological activities associated with individual severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) viral proteins, we found that ORF7a reduced cell surface MHC-I levels by approximately fivefold. Nevertheless, in cells infected with SARS-CoV-2, surface MHC-I levels were reduced even in the absence of ORF7a, suggesting additional mechanisms of MHC-I down-regulation. ORF7a proteins from a sample of sarbecoviruses varied in their ability to induce MHC-I down-regulation and, unlike SARS-CoV-2, the ORF7a protein from SARS-CoV lacked MHC-I downregulating activity. A single amino acid at position 59 (T/F) that is variable among sarbecovirus ORF7a proteins governed the difference in MHC-I downregulating activity. SARS-CoV-2 ORF7a physically associated with the MHC-I heavy chain and inhibited the presentation of expressed antigen to CD8 + T cells. Specifically, ORF7a prevented the assembly of the MHC-I peptide loading complex and caused retention of MHC-I in the endoplasmic reticulum. The differential ability of ORF7a proteins to function in this way might affect sarbecovirus dissemination and persistence in human populations, particularly those with infection- or vaccine-elicited immunity.

Prediction of Bovine coronavirus immune epitopes using selection and phylogenetic analysis

“…The reduced support for MHC-I epitopes by selection analysis and analysis of sequence data could be due to downregulation of the MHC-I presentation by BoCoV. HCoV OC43 22 and other coronaviruses have been shown to suppress MHC-I presentation 40,41 suggesting BoCoV could also downregulate MHC-I. This study has predicted several BoCoV immune epitopes and corroborated several of these in spike and HE with selection analysis and sequence data.…”

Immunopeptidome profiling of human coronavirus OC43-infected cells identifies CD4 T cell epitopes specific to seasonal coronaviruses or cross-reactive with SARS-CoV-2

“…Viruses have evolved many mechanisms to evade the immune system, including the downregulation of MHC proteins [44–46]. To assess the effect of OC43 infection on the expression of MHC-I and II on HEK293.CIITA cells, we evaluated the surface expression of HLA-ABC, HLA-DR, and HLA-DP after infection.…”

“…MHC-I down-regulation has not been previously reported for OC43, but is a common feature of many viruses [44–46], including SARS-CoV-2 [45,46,56,63]. Current understanding of SARS-CoV-2-induced MHC-I down-regulation points to a complex mechanism, with the involvement of several gene products: ORF3a reduces global trafficking of proteins including MHC-I [45], ORF6 inhibits induction of MHC-I by targeting the STAT1-IRF1-NLRC5 axis [63], ORF7a reduces cell-surface expression of MHC-I [45,46] by acting as β 2-microglobulin mimic to interact with MHC-I heavy chain and slow its egress through the endoplasmic reticulum [45], and ORF8 also has been reported to down-regulate surface MHC-I through a direct interaction, although the specific mechanism is unclear [56]. However, none of these SARS-COV-2 gene products have significant homology with OC43, and elucidating the mechanism by which OC43 down-regulates MHC-I expression will require further investigation.…”

SARS-CoV-2 ORF7a mutation found in BF.5 and BF.7 sublineages impacts its functions

“…SARS-CoV-2 ORF7a is a type-1 transmembrane protein with 121 amino acid residues, consisting of an N-terminal signaling region (residues 1-15), an immunoglobulin-like (Ig-like) ectodomain consisting of seven β-strands (strands A to G; residues 16-96), a transmembrane domain (TM) (97-116) and a C-terminal ER-retention motif (residues 117-121) (12). Major functions ascribed to SARS-CoV-2 ORF7a during infection include impairing the antiviral effect of host factors including Serine Incorporator 5 (SERINC5) (13) and BST2/tetherin (14), inhibiting the type I interferon (IFN-I) response (15, 16) and downregulating the levels of Major Histocompatibility Complex-I (MHC-I) (17, 18) on the cell surface. In addition, SARS-CoV-2 has been associated with the induction of autophagy (19) and apoptosis (20), and upregulation of inflammatory responses (12, 21).…”