Abstract
The gamma-herpesvirus Epstein-Barr virus (EBV) persists for life in infected individuals despite the presence of a strong immune response. During the lytic cycle of EBV many viral proteins are expressed, potentially allowing virally infected cells to be recognized and eliminated by CD8+ T cells. We have recently identified an immune evasion protein encoded by EBV, BNLF2a, which is expressed in early phase lytic replication and inhibits peptide- and ATP-binding functions of the transporter associated with antigen processing. Ectopic expression of BNLF2a causes decreased surface MHC class I expression and inhibits the presentation of indicator antigens to CD8+ T cells. Here we sought to examine the influence of BNLF2a when expressed naturally during EBV lytic replication. We generated a BNLF2a-deleted recombinant EBV (ΔBNLF2a) and compared the ability of ΔBNLF2a and wild-type EBV-transformed B cell lines to be recognized by CD8+ T cell clones specific for EBV-encoded immediate early, early and late lytic antigens. Epitopes derived from immediate early and early expressed proteins were better recognized when presented by ΔBNLF2a transformed cells compared to wild-type virus transformants. However, recognition of late antigens by CD8+ T cells remained equally poor when presented by both wild-type and ΔBNLF2a cell targets. Analysis of BNLF2a and target protein expression kinetics showed that although BNLF2a is expressed during early phase replication, it is expressed at a time when there is an upregulation of immediate early proteins and initiation of early protein synthesis. Interestingly, BNLF2a protein expression was found to be lost by late lytic cycle yet ΔBNLF2a-transformed cells in late stage replication downregulated surface MHC class I to a similar extent as wild-type EBV-transformed cells. These data show that BNLF2a-mediated expression is stage-specific, affecting presentation of immediate early and early proteins, and that other evasion mechanisms operate later in the lytic cycle.
Highlights
The detection and elimination of virally infected cells by the host immune system relies heavily upon CD8+ T cells recognizing peptides endogenously processed and presented by HLA class I molecules
In this study we have shown that CD8+ T cell recognition of immediate early and early lytic cycle antigens is dramatically increased in lymphoblastoid cell lines (LCLs) transformed with a mutant Epstein-Barr virus (EBV) lacking the immune evasion gene BNLF2a compared to the recognition of wild-type EBV transformed LCLs
This increase in recognition was conserved across different HLA-class I backgrounds and these effects were seen using multiple different CD8+ T cell specificities, reinforcing the role of BNLF2a in active immune evasion during EBV lytic cycle replication
Summary
The detection and elimination of virally infected cells by the host immune system relies heavily upon CD8+ T cells recognizing peptides endogenously processed and presented by HLA class I molecules. Many viruses have developed strategies to evade CD8+ T cell recognition in order to aid their transmission and persistence within hosts This is true for the herpesviruses; large double-stranded DNA viruses characterized by their ability to enter a latent state within specialized cells in their respective hosts, with this itself a form of immune evasion due to the transcriptional silencing of most if not all genes. The finding of immune evasion mechanisms in members of each of the three a-, b- and c-herpesvirus subfamilies highlights the strong immunological pressure these viruses are under These evasion strategies often subvert cellular processes involved in the generation and presentation of epitopes to T cells (reviewed in [3,4]). The importance of these processes is highlighted by the Author Summary
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
