Inhibition of antigen processing by the internal repeat region of the Epstein-Barr virus nuclear antigen-1.
The Epstein-Barr virus (EBV)-encoded nuclear antigen (EBNA1) is expressed in latently EBV-infected B lymphocytes that persist for life in healthy virus carriers, and is the only viral protein regularly detected in all malignancies associated with EBV. Major histocompatibility complex (MHC) class I-restricted, EBNA1-specific cytotoxic T lymphocyte (CTL) responses have not been demonstrated. Using recombinant vaccinia viruses encoding chimaeric proteins containing an immunodominant human leukocyte antigen A11-restricted CTL epitope, amino acids 416-424 of the EBNA4 protein, inserted within the intact EBNA1, or within an EBNA1 deletion mutant devoid of the internal Gly-Ala repetitive sequence, we demonstrate that the Gly-Ala repeats generate a cis-acting inhibitory signal that interferes with antigen processing and MHC class I-restricted presentation. Insertion of the Gly-Ala repeats downstream of the 416-424 epitope inhibited CTL recognition of a chimaeric EBNA4 protein. The results highlight a previously unknown mechanism of viral escape from CTL surveillance, and support the view that the resistance of cells expressing EBNA1 to rejection mediated by CTL is a critical requirement for EBV persistence and pathogenesis.
Levitskaya
J
J
Microbiology and Tumour Biology Center, Karolinska Institute, Stockholm, Sweden.
Coram
M
M
Levitsky
V
V
Imreh
S
S
Steigerwald-Mullen
P M
PM
Klein
G
G
Kurilla
M G
MG
Masucci
M G
MG
D017951:Antigen Presentation; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology*; D001483:Base Sequence; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D019309:Epstein-Barr Virus Nuclear Antigens; D005347:Fibroblasts; D015234:HLA-A Antigens / Q000276:immunology; D059870:HLA-A11 Antigen; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014616:Vaccinia virus / Q000235:genetics
D000956:Antigens, Viral; D004268:DNA-Binding Proteins; D000939:Epitopes; D019309:Epstein-Barr Virus Nuclear Antigens; D015234:HLA-A Antigens; D059870:HLA-A11 Antigen; D009838:Oligodeoxyribonucleotides; D011993:Recombinant Fusion Proteins