Human Papillomavirus (HPV) is the leading cause of cervical cancer. Nearly 200 HPV types have been identified, making it the most common sexually transmitted infection globally. High-risk HPV types, especially HPV-16 and HPV-18 can lead to persistent infections and cancer, accounting for around 70% of cervical cancer cases. Despite being immunogenic, HPV evades immune detection through slow replication, minimal inflammation, suppression of early gene expression, and interference with antigen processing.
The E5 protein from HPV-16 plays a key role in immune evasion by downregulating of immune protein (HLA-A and HLA-B) that are critical for cytotoxic T cell surveillance that can lead to viral escape. Interestingly, E5 does not affect the surface expression of immune proteins called HLA-C, making HLA-C a promising target for immunotherapy and vaccine design. Like the well-studied HLA-A and HLA-B, the more unknown HLA-C molecules can present viral peptides to T cell for viral clearance.
Understanding how HLA-C presents HPV-derived peptides and activate cytotoxic T cells hence provides a valuable insight for translational outcomes. We identified an HPV E5-derived peptide presented by both HLA-C*05:01 and HLA-C*08:02. We have also isolated an HPV-E5-specific T cell and sequenced its surface T cell receptor (TCR). Furthermore, we successfully solved the crystal structures of the E5 peptide presented by both HLA-C molecules, and in complex with the TCR. Affinity measurements revealed that the TCR binds more strongly to HLA-C*05:01-E5 than to HLA-C*08:02-E5. This helped us design TCR mutants with increased affinity for HLA-C*08:02-E5 to facilitate the development of structure-based, improved T cell therapeutics that would be capable of killing HPV-infected cancer cells, broadening the applicability of this TCR based approach.