Abstract
Recent studies have shown that virally encoded mRNA sequences of genome maintenance proteins from herpesviruses contain clusters of unusual structural elements, G-quadruplexes, which modulate viral protein synthesis. Destabilization of these G-quadruplexes can override the inhibitory effect on self-synthesis of these proteins. Here we show that the purine-rich repetitive mRNA sequence of Epstein-Barr virus encoded nuclear antigen 1 (EBNA1) comprising G-quadruplex structures, limits both the presentation of MHC class I-restricted CD8+ T cell epitopes by CD11c+ dendritic cells in draining lymph nodes and early priming of antigen-specific CD8+ T-cells. Destabilization of the G-quadruplex structures through codon-modification significantly enhanced in vivo antigen presentation and activation of virus-specific T cells. Ex vivo imaging of draining lymph nodes by confocal microscopy revealed enhanced antigen-specific T-cell trafficking and APC-CD8+ T-cell interactions in mice primed with viral vectors encoding a codon-modified EBNA1 protein. More importantly, these antigen-specific T cells displayed enhanced expression of the T-box transcription factor and superior polyfunctionality consistent with the qualitative impact of translation efficiency. These results provide an important insight into how viruses exploit mRNA structure to down regulate synthesis of their viral maintenance proteins and delay priming of antigen-specific T cells, thereby establishing a successful latent infection in vivo. Furthermore, targeting EBNA1 mRNA rather than protein by small molecules or antisense oligonucleotides will enhance EBNA1 synthesis and the early priming of effector T cells, to establish a more rapid immune response and prevent persistent infection.
Highlights
The interaction of a peptide-MHC class I complex on antigen presenting cells (APCs) with a T cell receptor (TCR) on CD8+ T cells, initiates the activation of antigen-specific CD8+ T cells [1]
These findings suggest a novel approach to therapeutic development through the use of antisense strategies or small molecules targeting EBNA1 mRNA structure
Other studies have clearly demonstrated that the purine-rich, glycine-alanine repeat (GAr) mRNA structure limits EBNA1 synthesis, resulting in decreased presentation of EBNA1 to specific CD8+ T cells [19,22]
Summary
The interaction of a peptide-MHC class I (pMHC-I) complex on antigen presenting cells (APCs) with a T cell receptor (TCR) on CD8+ T cells, initiates the activation of antigen-specific CD8+ T cells [1]. Recent in vitro studies from many groups have revealed that endogenously processed MHC class I-restricted epitopes are predominantly generated from rapidly degraded defective ribosomal products (DRiPs) rather than from the degradation of fulllength, stable viral proteins [2,3,4,5,6]. This process suggests that by regulating the production of antigen or DRiPs in host cells during viral infection we could beneficially influence the generation and presentation of MHC class I-restricted epitopes and the induction of antigen-specific immune responses.
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