title: T cell epitope mapping of JC polyoma virus-encoded proteome reveals reduced T cell responses in HLA-DRB1*04:01+ donors.
abstract: JC polyomavirus (JCV) infection is highly prevalent and usually kept in a persistent state without clinical signs and symptoms. It is only during immunocompromise and especially impaired CD4(+) T cell function in the brain, as seen in AIDS patients or natalizumab-treated multiple sclerosis patients, that JCV may cause progressive multifocal leukoencephalopathy (PML), an often life-threatening brain disease. Since CD4(+) T cells likely play an important role in controlling JCV infection, we here describe the T cell response to JCV in a group of predominantly HLA-DR-heterozygotic healthy donors (HD) by using a series of overlapping 15-mer peptides spanning all JCV-encoded open reading frames. We identified immunodominant epitopes and compared T cell responses with anti-JCV VP1 antibody production and with the presence of urinary viral shedding. We observed positive JCV-specific T cell responses in 28.6% to 77.6%, humoral immune response in 42.6% to 89.4%, and urinary viral shedding in 36.4% to 45.5% of HD depending on the threshold. Four immunodominant peptides were mapped, and at least one immunogenic peptide per HLA-DRB1 allele was detected in DRB1*01(+), DRB1*07(+), DRB1*11(+), DRB1*13(+), DRB1*15(+), and DRB1*03(+) individuals. We show for the first time that JCV-specific T cell responses may be directed not only against JCV VP1 and large T antigen but also against all other JCV-encoded proteins. Heterozygotic DRB1*04:01(+) individuals showed very low T cell responses to JCV together with normal anti-VP1 antibody levels and no urinary viral shedding, indicating a dominant-negative effect of this allele on global JCV-directed T cell responses. Our data are potentially relevant for the development of vaccines against JCV.
authors.affiliation: University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ilijas
authors.initials: I
authors.lastname: Jelcic
authors.forename: Lilian
authors.initials: L
authors.lastname: Aly
authors.forename: Thomas M C
authors.initials: TM
authors.lastname: Binder
authors.forename: Ivan
authors.initials: I
authors.lastname: Jelcic
authors.forename: Sílvia
authors.initials: S
authors.lastname: Bofill-Mas
authors.forename: Raquel
authors.initials: R
authors.lastname: Planas
authors.forename: Victoria
authors.initials: V
authors.lastname: Demina
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Eiermann
authors.forename: Thomas
authors.initials: T
authors.lastname: Weber
authors.forename: Rosina
authors.initials: R
authors.lastname: Girones
authors.forename: Mireia
authors.initials: M
authors.lastname: Sospedra
authors.forename: Roland
authors.initials: R
authors.lastname: Martin
mesh_terms: D000328:Adult; D000368:Aged; D000914:Antibodies, Viral / Q000097:blood; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000032:analysis*; D005260:Female; D059811:HLA-DRB1 Chains / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000032:analysis; D007577:JC Virus / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D020543:Proteome / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014556:Urine / Q000821:virology; D017201:Virus Shedding
chemical_list: D000914:Antibodies, Viral; D018984:Epitopes, T-Lymphocyte; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; D016056:Immunodominant Epitopes; D020543:Proteome