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    Messenger RNA Sequence Rather than Protein Sequence Determines the Level of Self-synthesis and Antigen Presentation of the EBV-encoded Antigen, EBNA1

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    Author
    Tellam, Judy T
    Lekieffre, Lea
    Zhong, Jie
    Lynn, David J
    Khanna, Rajiv
    Keyword
    Epstein-Barr-Virus
    Sarcoma-Associated Herpesvirus
    T-Cell Recognition
    Open Reading Frame
    Nuclear Antigen-1
    Kaposis-Sarcoma
    Simian Homologs
    Immune Evasion
    Endogenous Presentation
    Viral Evasion
    Date
    2012-12-27
    
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    URI
    http://hdl.handle.net/11019/335
    Citation
    Tellam JT, Lekieffre L, Zhong J, Lynn DJ, Khanna R (2012) Messenger RNA Sequence Rather than Protein Sequence Determines the Level of Self-synthesis and Antigen Presentation of the EBV-encoded Antigen, EBNA1. PLoS Pathog 8(12): e1003112. doi:10.1371/journal.ppat.1003112
    Abstract
    Viruses establishing persistent latent infections have evolved various mechanisms to avoid immune surveillance. The Epstein-Barr virus-encoded nuclear antigen, EBNA1, expressed in all EBV-associated malignancies, modulates its own protein levels at quantities sufficient to maintain viral infection but low enough so as to minimize an immune response by the infected host cell. This evasion mechanism is regulated through an internal purine-rich mRNA repeat sequence encoding glycine and alanine residues. In this study we assess the impact of the repeat's nucleotide versus peptide sequence on inhibiting EBNA1 self-synthesis and antigen presentation. We demonstrate that altered peptide sequences resulting from frameshift mutations within the repeat do not alleviate the immune-evasive function of EBNA1, suggesting that the repetitive purine-rich mRNA sequence itself is responsible for inhibiting EBNA1 synthesis and subsequent poor immunogenicity. Our comparative analysis of the mRNA sequences of the corresponding repeat regions of different gammaherpesvirus maintenance homologues to EBNA1 highlights the high degree of identity between the nucleotide sequences despite very little homology in the encoded amino acid sequences. These studies demonstrate the importance of gammaherpesvirus purine-rich mRNA repeat sequences on antigenic epitope generation and evasion from T-cell mediated immune control, suggesting novel approaches to prevention and treatment of latent infection by this class of virus.
    Funder
    National Health & Medical Research Council Australia
    Grant Number
    496684 APP1005091; 496712
    ae974a485f413a2113503eed53cd6c53
    http://dx.doi.org/10.1371/journal.ppat.1003112
    Scopus Count
    Collections
    Animal & Bioscience

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