title: Measles Virus Epitope Presentation by HLA: Novel Insights into Epitope Selection, Dominance, and Microvariation.
abstract: Immunity to infections with measles virus (MV) can involve vigorous human leukocyte antigen (HLA) class I-restricted CD8(+) cytotoxic T cell (CTL) responses. MV, albeit regarded monotypic, is known to undergo molecular evolution across its RNA genome. To address which regions of the MV proteome are eligible for recognition by CD8(+) CTLs and how different HLA class I loci contribute to the epitope display, we interrogated the naturally processed and presented MV peptidome extracted from cell lines expressing in total a broad panel of 16 different common HLA-A, -B, and -C molecules. The repertoire and abundance of MV peptides were bona fide identified by nanoHPLC-MS/MS. -Eighty-nine MV peptides were discovered and assignment to an HLA-A, -B, or -C allele, based on HLA-peptide affinity prediction, was in most cases successful. Length variation and presentation by multiple HLA class I molecules was common in the MV peptidome. More than twice as many unique MV epitopes were found to be restricted by HLA-B than by HLA-A, while MV peptides with supra-abundant expression rates (>5,000 cc) were rather associated with HLA-A and HLA-C. In total, 59 regions across the whole MV proteome were identified as targeted by HLA class I. Sequence coverage by epitopes was highest for internal proteins transcribed from the MV-P/V/C and -M genes and for hemagglutinin. At the genome level, the majority of the HLA class I-selected MV epitopes represented codons having a higher non-synonymous mutation rate than silent mutation rate, as established by comparison of a set of 58 unique full length MV genomes. Interestingly, more molecular variation was seen for the epitopes expressed at rates ≥1,000 cc. These data for the first time indicate that HLA class I broadly samples the MV proteome and that CTL pressure may contribute to the genomic evolution of MV.
authors.affiliation: Centre for Infectious Disease Control, National Institute for Public Health and the Environment , Bilthoven , Netherlands ; Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht , Utrecht , Netherlands ; Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht , Utrecht , Netherlands.
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Schellens
authors.affiliation: Institute for Translational Vaccinology , Bilthoven , Netherlands.
authors.forename: Hugo D
authors.initials: HD
authors.lastname: Meiring
authors.affiliation: Theoretical Biology and Bioinformatics, Utrecht University , Utrecht , Netherlands.
authors.forename: Ilka
authors.initials: I
authors.lastname: Hoof
authors.affiliation: Centre for Infectious Disease Control, National Institute for Public Health and the Environment , Bilthoven , Netherlands ; Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht , Utrecht , Netherlands ; Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht , Utrecht , Netherlands.
authors.forename: Sanne N
authors.initials: SN
authors.lastname: Spijkers
authors.affiliation: Centre for Infectious Disease Control, National Institute for Public Health and the Environment , Bilthoven , Netherlands.
authors.forename: Martien C M
authors.initials: MC
authors.lastname: Poelen
authors.affiliation: Centre for Infectious Disease Control, National Institute for Public Health and the Environment , Bilthoven , Netherlands.
authors.forename: Jacqueline A M
authors.initials: JA
authors.lastname: van Gaans-van den Brink
authors.affiliation: Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht , Utrecht , Netherlands ; Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht , Utrecht , Netherlands.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Costa
authors.affiliation: Centre for Infectious Disease Control, National Institute for Public Health and the Environment , Bilthoven , Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: Vennema
authors.affiliation: Theoretical Biology and Bioinformatics, Utrecht University , Utrecht , Netherlands.
authors.forename: Can
authors.initials: C
authors.lastname: Keşmir
authors.affiliation: Centre for Infectious Disease Control, National Institute for Public Health and the Environment , Bilthoven , Netherlands ; Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht , Utrecht , Netherlands ; Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht , Utrecht , Netherlands.
authors.forename: Debbie
authors.initials: D
authors.lastname: van Baarle
authors.affiliation: Centre for Infectious Disease Control, National Institute for Public Health and the Environment , Bilthoven , Netherlands.
authors.forename: Cécile A C M
authors.initials: CA
authors.lastname: van Els
keywords: CD8 T cell epitope; HLA class I; HLA-A antigens; HLA-B antigens; HLA-C antigens; epitope mapping; immunodominance; measles virus