SARS-CoV-2 open reading frame 3a protein-derived peptides presented on major histocompatibility complex (SARS-CoV-2 ORF3a-pMHC)

SARS-CoV-2 ORF3a protein-derived peptides presented on the Major Histocompatibility Complex (MHC) are essential targets for cellular immunity against COVID-19 (Grifoni et al., 2020, Cell). The ORF3a protein is a multi-functional accessory protein that acts as a viroporin, altering membrane permeability and promoting viral egress while also triggering apoptosis and the NLRP3 inflammasome (UniProt P0DTC3; Siu et al., 2019). During the viral life cycle, ORF3a is degraded by the proteasome into peptides that are subsequently presented on the cell surface by MHC Class I or Class II molecules (Saini et al., 2021, Science Immunology). These peptide-MHC (pMHC) complexes serve as the primary signal for T-cell recognition, allowing CD8+ cytotoxic T cells to identify and destroy infected host cells (Le Bert et al., 2020, Nature). Because ORF3a is relatively conserved compared to the Spike protein, these pMHC complexes are being investigated as targets for next-generation COVID-19 vaccines and TCR-engineered T-cell therapies (Quadeer et al., 2021). Therapeutic strategies focusing on these targets aim to provide robust, long-term immunity that is less susceptible to the mutational escape observed with antibody-focused treatments (Tarke et al., 2021, Cell Reports Medicine). Research has identified specific immunodominant epitopes within ORF3a, such as those restricted by HLA-A*01:01, which are highly effective at eliciting T-cell responses (Lineburg et al., 2021, Immunity).

Other names

ORF3a peptide-HLA complexSARS-CoV-2 ORF3a T-cell epitopesSARS-CoV-2 viroporin 3a-derived MHC-presented peptidesORF3a-MHC I complex

T-cell receptor (TCR) mediated recognition of the peptide-MHC complex leading to cytotoxic T-lymphocyte (CTL) activation and apoptosis of the target cell.