Translation efficiency of EBNA1 encoded by lymphocryptoviruses influences endogenous presentation of CD8⁺ T cell epitopes

Abstract

Lymphocryptoviruses (LCV) that infect humans and Old World primates display a significant degree of genetic identity. These viruses use B lymphocytes as primary host cells to establish a long-term latent infection and express highly homologous latent viral proteins. Of particular interest is the expression of the EBV-encoded nuclear antigen-1 (EBNA1), which plays a crucial role in maintaining the viral genome in B cells. Using human and Old World primate homologues of EBNA1, we show that the internal repeat sequences differentially influence their in vitro translation efficiency. Although the glycine-alanine repeat domain of human LCV (EBV) EBNA1 inhibits its self-synthesis, the repeat domains within the simian LCV homologues of EBNA1 do not inhibit selfsynthesis. As a consequence, simian LCV EBNA1-expressing cells are more efficiently recognized by virus-specific CTL when compared to human EBV EBNA1, even though both proteins are highly stable in B cells. Interestingly, we also show that similar to human EBNA1, CD8 + T cell epitopes from simian LCV EBNA1 are predominantly derived from newly synthesized protein rather than the long-lived pool of stable protein. These observations provide additional evidence that supports the theory that immune recognition of EBNA1 can occur without compromising the biological maintenance function of this protein.

Expression of HPV 58 Long and Short L1 Capsid Proteins in Primary Mouse Keratinocyte Cultures

“…These data were consistent with recent studies on differential expression of nuclear antigen 1 protein gene (EBNA1) in Epstein-Barr virus, with or without an internal glycine-alanine repeat sequence [35,36]. But, what mechanisms might determine the different translation efficiencies of the viral genes examined in our and other studies?…”

Acquisition of Polyfunctionality by Epstein-Barr Virus-Specific CD8 + T Cells Correlates with Increased Resistance to Galectin-1-Mediated Suppression

“…This is potentially driven by the ability of these antigens to limit self-processing and presentation via the MHC-I pathway and subsequent poor priming following infection (29)(30)(31). Although the mechanism which rendered LMP-and EBNA1-specific T cells more susceptible to Gal-1 was not elucidated in this study, it does provide evidence that qualitative differences in T cells can be associated with differences in susceptibility to immunosuppression.…”

“…There is increasing evidence that the LMP-1/2 and EBNA1 antigens have developed strategies to limit their presentation to T cells (29)(30)(31). This reduction in recognition of endogenous antigen could potentially influence the priming of T cells against LMP-1/2 and EBNA1, inducing a quantitatively and qualitatively inferior response.…”

mRNA Translation Regulation by the Gly-Ala Repeat of Epstein-Barr Virus Nuclear Antigen 1

“…For example, EBV-infected individuals carry CD8 ϩ T cells toward EBNA-1 epitopes, but these T cells fail to recognize and kill EBNA-1-expressing cells due to the effect of the GAr on mRNA translation (1,19). So, disrupting the mechanisms of action of the GAr via therapeutic intervention has the potential to increase the presentation of viral antigens on MHC class I molecules and thereby to trigger an immune reaction toward virus-carrying tumor cells.…”

“…Independent studies suggest that both proteins have evolved mechanisms to remain largely invisible to the immune system, which could otherwise eliminate latently infected cells (8,9,19,25). These mechanisms act in cis and are mediated via an internal repeat region.…”