Epstein Barr Virus-Encoded EBNA1 Interference with MHC Class I Antigen Presentation Reveals a Close Correlation between mRNA Translation Initiation and Antigen Presentation

Abstract

Viruses are known to employ different strategies to manipulate the major histocompatibility (MHC) class I antigen presentation pathway to avoid recognition of the infected host cell by the immune system. However, viral control of antigen presentation via the processes that supply and select antigenic peptide precursors is yet relatively unknown. The Epstein-Barr virus (EBV)-encoded EBNA1 is expressed in all EBV-infected cells, but the immune system fails to detect and destroy EBV-carrying host cells. This immune evasion has been attributed to the capacity of a Gly-Ala repeat (GAr) within EBNA1 to inhibit MHC class I restricted antigen presentation. Here we demonstrate that suppression of mRNA translation initiation by the GAr in cis is sufficient and necessary to prevent presentation of antigenic peptides from mRNAs to which it is fused. Furthermore, we demonstrate a direct correlation between the rate of translation initiation and MHC class I antigen presentation from a certain mRNA. These results support the idea that mRNAs, and not the encoded full length proteins, are used for MHC class I restricted immune surveillance. This offers an additional view on the role of virus-mediated control of mRNA translation initiation and of the mechanisms that control MHC class I restricted antigen presentation in general.

Author Summary

The presentation of short peptides on major histocompatibility (MHC) class I molecules forms the cornerstone for which the immune system tells apart self from non-self. It is important for viruses such as the Epstein-Barr virus (EBV) to avoid this antigen presentation pathway in order to escape recognition and killing of its host cells. All EBV-infected cells, including cancer cells, express EBNA1 without attracting the attention of the immune system. In this report we describe the mechanism by which EBNA1 escapes antigen presentation. This should open up for new approaches to target EBV-associated diseases including cancers and immuno proliferative disorders and for understanding the underlying mechanisms of the source and regulation of antigenic peptide production.