Epstein Barr virus-encoded EBNA1 interference with MHC class I antigen presentation reveals a close correlation between mRNA translation initiation and antigen presentation

PLoS Pathog. 2010 Oct 14;6(10):e1001151. doi: 10.1371/journal.ppat.1001151.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation / genetics*
  • Antigen Presentation / immunology
  • Base Sequence
  • Cell Line, Tumor
  • Dipeptides / chemistry
  • Dipeptides / immunology
  • Epstein-Barr Virus Nuclear Antigens / chemistry
  • Epstein-Barr Virus Nuclear Antigens / genetics
  • Epstein-Barr Virus Nuclear Antigens / physiology*
  • Eukaryotic Initiation Factors / metabolism
  • Eukaryotic Initiation Factors / physiology
  • Herpesvirus 4, Human / genetics
  • Herpesvirus 4, Human / immunology*
  • Histocompatibility Antigens Class I / immunology
  • Histocompatibility Antigens Class I / metabolism*
  • Host-Pathogen Interactions / genetics
  • Host-Pathogen Interactions / immunology
  • Humans
  • Immune Evasion / genetics*
  • Immune Evasion / immunology
  • Immunodominant Epitopes / chemistry
  • Immunodominant Epitopes / immunology
  • Mice
  • Models, Biological
  • Nucleic Acid Conformation
  • Protein Biosynthesis / genetics
  • Protein Biosynthesis / immunology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • Repetitive Sequences, Amino Acid / immunology
  • Repetitive Sequences, Amino Acid / physiology

Substances

  • Dipeptides
  • Epstein-Barr Virus Nuclear Antigens
  • Eukaryotic Initiation Factors
  • Histocompatibility Antigens Class I
  • Immunodominant Epitopes
  • RNA, Messenger
  • N-glycylalanine
  • EBV-encoded nuclear antigen 1