8rnh
Crystal structure of HLA B*18:01 in complex with EEIEITTHF, an 9-mer epitope from Influenza A
Structural highlights
FunctionRDRP_I78A8 RNA-dependent RNA polymerase which is responsible for replication and transcription of virus RNA segments. The transcription of viral mRNAs occurs by a unique mechanism called cap-snatching. 5' methylated caps of cellular mRNAs are cleaved after 10-13 nucleotides by PA. In turn, these short capped RNAs are used as primers by PB1 for transcription of viral mRNAs. During virus replication, PB1 initiates RNA synthesis and copy vRNA into complementary RNA (cRNA) which in turn serves as a template for the production of more vRNAs.[HAMAP-Rule:MF_04065] Publication Abstract from PubMedOBJECTIVES: Seasonal influenza viruses cause roughly 650 000 deaths annually despite available vaccines. CD8(+) T cells typically recognise influenza-derived peptides from internal structural and non-structural influenza proteins and are an attractive avenue for future vaccine design as they could reduce the severity of disease following infection with diverse influenza strains. CD8(+) T cells recognise peptides presented by the highly polymorphic Human Leukocyte Antigens class I molecules (HLA-I). Each HLA-I variant has distinct peptide binding preferences, representing a significant obstacle for designing vaccines that elicit CD8(+) T cell responses across broad populations. Consequently, the rational design of a CD8(+) T cell-mediated vaccine would require the identification of highly immunogenic peptides restricted to a range of different HLA molecules. METHODS: Here, we assessed the immunogenicity of six recently published novel influenza-derived peptides identified by mass-spectrometry and predicted to bind to the prevalent HLA-B*18:01 molecule. RESULTS: Using CD8(+) T cell activation assays and protein biochemistry, we showed that 3/6 of the novel peptides were immunogenic in several HLA-B*18:01(+) individuals and confirmed their HLA-B*18:01 restriction. We subsequently compared CD8(+) T cell responses towards the previously identified highly immunogenic HLA-B*18:01-restricted NP(219) peptide. Using X-ray crystallography, we solved the first crystal structures of HLA-B*18:01 presenting immunogenic influenza-derived peptides. Finally, we dissected the first TCR repertoires specific for HLA-B*18:01 restricted pathogen-derived peptides, identifying private and restricted repertoires against each of the four peptides. CONCLUSION: Overall the characterisation of these novel immunogenic peptides provides additional HLA-B*18:01-restricted vaccine targets derived from the Matrix protein 1 and potentially the non-structural protein and the RNA polymerase catalytic subunit of influenza viruses. Characterisation of novel influenza-derived HLA-B*18:01-restricted epitopes.,Leong SL, Murdolo L, Maddumage JC, Koutsakos M, Kedzierska K, Purcell AW, Gras S, Grant EJ Clin Transl Immunology. 2024 May 10;13(5):e1509. doi: 10.1002/cti2.1509. , eCollection 2024. PMID:38737448[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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