Viral peptide–Human Leukocyte Antigen complex (pHLA)

Viral peptide–Human Leukocyte Antigen (HLA) complexes are molecular assemblies presented on the surface of infected cells, serving as the primary signal for the adaptive immune system to detect intracellular pathogens (Rock et al., 2016, PMID: 26773482). These complexes are formed when viral proteins are degraded by the proteasome into short peptides, which are then transported into the endoplasmic reticulum and loaded onto HLA Class I or II molecules (Blum et al., 2013, PMID: 23273551). Once displayed on the cell surface, they are recognized by specific T-cell receptors (TCRs) on cytotoxic T lymphocytes, leading to the targeted destruction of the infected cell (Janeway et al., 2001). In drug development, these complexes are highly attractive targets because they allow for the recognition of internal viral proteins that are not accessible to traditional antibodies (Joglekar & Li, 2021, PMID: 33398162). Therapeutic strategies include TCR-engineered T cells (TCR-T), chimeric antigen receptor T cells (CAR-T) designed to mimic TCR specificity, and bispecific T-cell engagers like ImmTAVs (Liddy et al., 2012, PMID: 22561687). Targeting these complexes enables high specificity against viral-infected cells while sparing healthy tissue, provided the peptide is unique to the virus (Spear et al., 2016, PMID: 26903154). However, the high polymorphism of HLA alleles across the human population requires these therapies to be HLA-restricted, often limiting their use to specific patient subsets (Borbulevych et al., 2007, PMID: 17513741). Challenges in targeting these complexes include the risk of cross-reactivity with similar self-peptides and the potential for viruses to downregulate HLA expression to evade immune detection (Linette et al., 2013, PMID: 23770690; Hansen & Bouvier, 2009, PMID: 19413887).

Other names

pMHCPeptide-MHC complexViral antigen-HLA complexMHC-restricted viral antigenPeptide-Human Leukocyte Antigen complex

T-cell receptor (TCR) mediated recognition and subsequent T-cell activation leading to lysis of infected cells (Liddy et al., 2012; Joglekar & Li, 2021).