Nature 375, 685 - 688 (22 June 1995); doi:10.1038/375685a0

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

Jelena Levitskaya^*, Michael Coram^†, Victor Levitsky^*, Stefan Imreh^*, Patty M. Steigerwald-Mullen^†, George Klein^*, Michael G. Kurilla^† & Maria G. Masucci^*‡

^* Microbiology and Tumour Biology Center, Karolinska Institute, S-171 77 Stockholm, Sweden
^†Department of Pathology, University of Virginia Health Science Center, Charlottenville, Virginia 22908,USA

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^1,2, and is the only viral protein regularly detected in all malignancies associated with EBV^3,4. Major histocompatibility complex (MHC) class I-restricted, EBNA1-specific cytotoxic T lymphocyte (CTL) responses have not been demonstrated^3,5. 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.

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