SARS-CoV-2 Omicron subvariants evolved to promote further escape from MHC-I recognition

Moriyama, Miyu; Lucas, Carolina; Monteiro, Valter Silva; Iwasaki, Akiko

doi:10.1101/2022.05.04.490614

Cited by 17 publications

(21 citation statements)

References 73 publications

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“…Two days after transduction of human 293T cells, we measured MHC-I surface levels by flow cytometry using a pan-HLA class I-reactive monoclonal antibody. Expression of ORF7a reduced MHC-I levels on the cell surface by approximately 5-fold, whereas expression of other individual viral proteins (notably including ORF8 (16, 17)) had no effect on MHC-I surface levels (Figure 1). We also examined the impact of SARS-CoV-2 ORFs on the expression of tetherin, a cell surface antiviral protein that traps enveloped virions from various virus families that bud through cell membranes.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, there are several reasons to think that MHC-I downregulation might be an evolved property in sarbecoviruses. Some recent studies have suggested that SARS-CoV-2 ORF8 protein induces MHC-I downregulation(16, 17). We did not observe such an effect.…”

Section: Discussionmentioning

confidence: 99%

“…Analysis of coronavirus-host proteinprotein interactions, using affinity- or proximity-based approaches, has suggested that several viral proteins (ORF3a, ORF3b, ORF7a, ORF8, M, and nsp4) associate with host proteins that are enriched in endoplasm reticulum (ER) or Golgi, the organelles where viral peptides are loaded onto MHC-I molecule and transported to the cell surface for presentation to CD8+ T-cells (14, 15). Moreover, Some reports have indicated that SARS-CoV-2 ORF8 reduces expression of MHC-I on the surface of infected cells (16, 17). Here we show that SARS-CoV-2 ORF7a can inhibit antigen presentation by preventing the assembly of the MHC-I peptide loading complex and causing retention of MHC-I in the endoplasmic reticulum.…”

Section: Introductionmentioning

confidence: 99%

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

Zhang

Zang

Stevenson

et al. 2022

Preprint

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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 SARS-CoV-2 viral proteins, we found that ORF7a reduced cell surface MHC-I levels by approximately 5-fold. 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 downregulation. ORF7a proteins from a sample of sarbecoviruses varied in their ability to induce MHC-I downregulation 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. Speficially, ORF7a prevented the assembly of the MHC-I peptide loading complex and causing 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.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Zhang

Zang

Stevenson

et al. 2022

Preprint

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“…Given the functional consequence of localization of ORF7a we have observed, we suggest that studies employing C-terminally tagged ORF7a need to be interpreted with caution. However, a recent report that has not been peer-reviewed found that C-terminally tagged ORF7a was capable of downregulating MHC-I in HEK293T cells(37). While we expressed ORF7a-ARA in an inducible manner, the tagged ORF7a was transiently expressed, and we are investigating whether this or other mechanisms account for this difference.…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 accessory proteins ORF7a and ORF3a use distinct mechanisms to downregulate MHC-I surface expression

Arshad

Laurent-Rolle

Ahmed

et al. 2022

Preprint

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Major histocompatibility complex class I (MHC-I) molecules, which are dimers of a glycosylated polymorphic transmembrane heavy chain and the small protein β2-microglobulin (β2m), bind peptides in the endoplasmic reticulum that are generated by the cytosolic turnover of cellular proteins. In virus-infected cells these peptides may include those derived from viral proteins. Peptide-MHC-I complexes then traffic through the secretory pathway and are displayed at the cell surface where those containing viral peptides can be detected by CD8+ T lymphocytes that kill infected cells. Many viruses enhance their in vivo survival by encoding genes that downregulate MHC-I expression to avoid CD8+ T cell recognition. Here we report that two accessory proteins encoded by SARS-CoV-2, the causative agent of the ongoing COVID-19 pandemic, downregulate MHC-I expression using distinct mechanisms. One, ORF3a, a viroporin, reduces global trafficking of proteins, including MHC-I, through the secretory pathway. The second, ORF7a, interacts specifically with the MHC-I heavy chain, acting as a molecular mimic of β2m to inhibit its association. This slows the exit of properly assembled MHC-I molecules from the endoplasmic reticulum. We demonstrate that ORF7a reduces antigen presentation by the human MHC-I allele HLA-A*02:01. Thus, both ORF3a and ORF7a act post-translationally in the secretory pathway to lower surface MHC-I expression, with ORF7a exhibiting a novel and specific mechanism that allows immune evasion by SARS-CoV-2.Significance StatementViruses may down-regulate MHC class I expression on infected cells to avoid elimination by cytotoxic T cells. We report that the accessory proteins ORF7a and ORF3a of SARS-CoV-2 mediate this function and delineate the two distinct mechanisms involved. While ORF3a inhibits global protein trafficking to the cell surface, ORF7a acts specifically on MHC-I by competing with β2m for binding to the MHC-I heavy chain. This is the first account of molecular mimicry of β2m as a viral mechanism of MHC-I down-regulation to facilitate immune evasion.

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“…Besides ORF7a, multiple studies have identified SARS-CoV-2 gene products to interfere with MHC-I expression. A recent preprint showed that several SARS-CoV-2 gene products have the capacity to downregulate MHC-I molecules, including the viral E, M, ORF7a, ORF7b, and ORF8 proteins [51]. In this study, no additional experiments were performed to address the nature of MHC-I regulation.…”

Section: Discussionmentioning

confidence: 99%

The SARS-CoV-2 accessory factor ORF7a downregulates MHC class I surface expression

Zheng¹,

Buhr²,

Praest³

et al. 2022

Preprint

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The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in over 500 million infections and more than six million deaths worldwide. Although the viral genomes of SARS-CoV-1 and SARS-CoV-2 share high sequence homology, the clinical and pathological features of COVID-19 differ profoundly from those of SARS. It is apparent that changes in viral genes contribute to the increased transmissibility of SARS-CoV-2 and pathology of COVID-19. Cytotoxic T lymphocytes play a key role in the elimination of virus-infected cells, mediated by recognition of virus-derived peptides that are presented on MHC class I molecules. Here, we show that SARS-CoV-2 can interfere with antigen presentation thereby evading immune surveillance. SARS-CoV-2 infection of monkey and human cell lines resulted in reduced cell-surface expression of MHC class I molecules. We identified a single viral gene product, the accessory factor open reading frame 7a (ORF7a), that mediates this effect. ORF7a interacts with HLA class I molecules in the ER, resulting in ER retention or impaired HLA heavy chain (HC) trafficking to the Golgi. Ultimately, these actions result in reduced HLA class I surface expression on infected cells. Whereas ORF7a from SARS-CoV-2 reduces surface HLA class I levels, the homologous ORF7a from the 2002 pandemic SARS-CoV-1 did not, suggesting that SARS-CoV-2 ORF7a acquired the ability to downregulate HLA-I during evolution of the virus. We identified a single amino acid in the SARS-CoV-1 ORF7a luminal domain that, upon mutating to the corresponding SARS-CoV-2 ORF7a sequence, induced a gain-of-function in HLA surface downregulation. By abrogating HLA class I antigen presentation via ORF7a, SARS-CoV-2 may evade host immune responses by inhibiting anti-viral cytotoxic T cell activity, thereby contributing to the pathology of COVID-19.

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SARS-CoV-2 Omicron subvariants evolved to promote further escape from MHC-I recognition

Cited by 17 publications

References 73 publications

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

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

SARS-CoV-2 accessory proteins ORF7a and ORF3a use distinct mechanisms to downregulate MHC-I surface expression

The SARS-CoV-2 accessory factor ORF7a downregulates MHC class I surface expression

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