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

Proc Natl Acad Sci U S A. 2022 Oct 11;119(41):e2209042119. doi: 10.1073/pnas.2209042119. Epub 2022 Sep 22.

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.

Keywords: MHC-I down-regulation; ORF7a; Peptide loading complex; SARS-CoV-2; Sarbecovirus.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acids
  • Antigen Presentation*
  • CD8-Positive T-Lymphocytes* / immunology
  • COVID-19* / immunology
  • Histocompatibility Antigens Class I* / immunology
  • Humans
  • Major Histocompatibility Complex
  • Peptides
  • SARS-CoV-2
  • Viral Proteins* / immunology

Substances

  • Amino Acids
  • Histocompatibility Antigens Class I
  • ORF7a protein, SARS-CoV-2
  • Peptides
  • Viral Proteins