Viral antigen–specific peptide–Human Leukocyte Antigen complex (pHLA complex)

Viral antigen–specific peptide–Human Leukocyte Antigen (pHLA) complexes are molecular assemblies displayed on the surface of cells that have been infected by viruses (Murphy & Weaver, Janeway's Immunobiology, 2016). These complexes are formed when intracellular viral proteins are degraded by the proteasome into short peptides, which are then transported into the endoplasmic reticulum and loaded onto HLA (MHC) molecules (Rock et al., Nature Immunology, 2016). The primary biological role of the pHLA complex is to act as a signal to the adaptive immune system, specifically allowing CD8+ T-cells to identify and eliminate infected host cells (Restifo et al., Nature Reviews Immunology, 2012). Recognition occurs through the binding of a T-cell receptor (TCR) to both the viral peptide and the surrounding HLA structure, ensuring high specificity (Rossjohn et al., Annual Review of Immunology, 2015). In clinical applications, these complexes are targeted by advanced immunotherapies such as TCR-engineered T-cell (TCR-T) therapies and TCR-mimetic antibodies to treat chronic infections and viral-induced cancers (Qiao et al., Frontiers in Immunology, 2022). For example, therapies targeting HPV-E6 or HBV-surface antigen peptides presented by HLA-A*02:01 are currently in clinical development (Draper et al., Clinical Cancer Research, 2015). A significant challenge in targeting pHLA complexes is the high degree of HLA polymorphism in the human population, requiring treatments to be matched to a patient's specific HLA type (Bielska et al., Frontiers in Immunology, 2020). Additionally, viruses may evolve to downregulate HLA expression or mutate the target peptide to evade immune detection, a process known as immune escape (Hansen & Bouvier, Trends in Immunology, 2009).

Other names

Peptide-MHC complexpMHCViral peptide-HLA complexHLA-restricted viral antigenMHC-peptide complex

Therapeutic agents, such as TCR-T cells or TCR-mimetic antibodies, bind specifically to the viral peptide-HLA complex on the cell surface, triggering the release of cytotoxic granules (perforin and granzymes) and inflammatory cytokines (IFN-gamma, TNF-alpha), which leads to the targeted lysis of the infected cell (June et al., Science, 2018; Rossjohn et al., Annual Review of Immunology, 2015).