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

SARS-CoV-2 open reading frame 3a (ORF3a) is a viral accessory protein that functions as a viroporin, playing a critical role in viral replication, virion release, and the induction of host cell apoptosis and NLRP3 inflammasome activation (UniProt P0DTC3). During infection, ORF3a is processed by the host cell's proteasome into short peptide fragments, which are then loaded onto Major Histocompatibility Complex (MHC) molecules and presented on the cell surface. These peptide-MHC (pMHC) complexes are essential targets for the cellular immune response, as they allow CD8+ cytotoxic T lymphocytes to identify and eliminate infected cells (Grifoni et al., 2020, Cell). Unlike the Spike protein, which is subject to high mutational pressure from neutralizing antibodies, ORF3a is relatively conserved, making its MHC-presented peptides attractive targets for next-generation vaccines and T-cell receptor (TCR)-based immunotherapies. Therapeutic development focuses on identifying immunodominant epitopes, such as those restricted by common alleles like HLA-A*02:01, to provide broad and durable protection against multiple SARS-CoV-2 variants.

Other names

ORF3a-derived epitopesSARS-CoV-2 ORF3a HLA-restricted peptidesORF3a peptide-MHC complexSARS-CoV-2 viroporin-derived antigens

Recognition of the specific peptide-MHC complex by the T-cell receptor (TCR) of CD8+ cytotoxic T lymphocytes, leading to the targeted lysis of SARS-CoV-2 infected cells and the release of pro-inflammatory cytokines.