title: T cell responses and virus evolution: loss of HLA A11-restricted CTL epitopes in Epstein-Barr virus isolates from highly A11-positive populations by selective mutation of anchor residues.
abstract: Epstein-Barr virus (EBV) is a B lymphotropic herpesvirus of humans that elicits strong HLA class I-restricted cytotoxic T lymphocyte (CTL) responses. An influence of such responses on virus evolution was first suggested by our finding that EBV isolates from the highly HLA A11-positive Papua New Guinea (PNG) population carried a lys-thr mutation at residue 424 of the nuclear antigen EBV-encoded nuclear antigen (EBNA4) that destroyed the immunodominant target epitope for A11-restricted CTL recognition. Here we turn to a much larger population, Southern Chinese, where the A11 allele is again present in over 50% of the individuals. Each of 23 EBV isolates analyzed from this population were also mutated in the EBNA4 416-424 epitope, the mutations selectively involving one of the two anchor residues in positions 2 (417 val-leu) or 9 (424 lys-asp, -arg or -thr) that are critical for A11-peptide interaction. The majority of the Chinese isolates and all 10 PNG isolates also carried mutations affecting positions 1 and 2 of the next most immunodominant A11-restricted epitope, EBNA4 residues 399-408. These changes clearly affected antigenicity since A11-positive lymphoblastoid cell lines (LCLs) carrying these mutant EBV strains were not recognized by A11-restricted CTLs raised against the prototype B95.8 virus. Furthermore, Chinese donors naturally infected with these mutant viruses did not mount detectable A11-restricted CTL responses on in vitro stimulation with autologous LCL cells carrying either the B95.8 or their endogenous EBV strain. In two different highly A11-positive populations, therefore, immune pressure appears to have selected for resident EBV strains lacking immunodominant A11-restricted CTL epitopes.
authors.affiliation: Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden.
authors.forename: P O
authors.initials: PO
authors.lastname: de Campos-Lima
authors.forename: V
authors.initials: V
authors.lastname: Levitsky
authors.forename: J
authors.initials: J
authors.lastname: Brooks
authors.forename: S P
authors.initials: SP
authors.lastname: Lee
authors.forename: L F
authors.initials: LF
authors.lastname: Hu
authors.forename: A B
authors.initials: AB
authors.lastname: Rickinson
authors.forename: M G
authors.initials: MG
authors.lastname: Masucci
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D005075:Biological Evolution; D002051:Burkitt Lymphoma / Q000382:microbiology; D002681:China; D004279:DNA, Viral; D000939:Epitopes / Q000276:immunology; D005006:Ethnicity; D015234:HLA-A Antigens / Q000276:immunology*; D059870:HLA-A11 Antigen; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D004279:DNA, Viral; D000939:Epitopes; D015234:HLA-A Antigens; D059870:HLA-A11 Antigen