Inhibition of antigen processing by the internal repeat region of the Epstein–Barr virus nuclear antigen-1

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Abstract
THE Epstein–Barr virus (EBV)-encoded nuclear antigen (EBNA1) is expressed in latently EBV-infected B lymphocytes that persist for life in healthy virus carriers1,2, and is the only viral protein regularly detected in all malignancies associated with EBV3,4. Major histocompatibility complex (MHC) class I-restricted, EBNA1-specific cytotoxic T lymphocyte (CTL) responses have not been demonstrated3,5. Using recombinant vaccinia viruses encoding chimaeric proteins containing an immunodominant human leukocyte antigen All-restricted CTL epitope, amino acids 416–424 of the EBNA4 protein6, 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.