Abstract
CD8+ T cell responses to Epstein-Barr virus (EBV) lytic cycle expressed antigens display a hierarchy of immunodominance, in which responses to epitopes of immediate-early (IE) and some early (E) antigens are more frequently observed than responses to epitopes of late (L) expressed antigens. It has been proposed that this hierarchy, which correlates with the phase-specific efficiency of antigen presentation, may be due to the influence of viral immune-evasion genes. At least three EBV-encoded genes, BNLF2a, BGLF5 and BILF1, have the potential to inhibit processing and presentation of CD8+ T cell epitopes. Here we examined the relative contribution of these genes to modulation of CD8+ T cell recognition of EBV lytic antigens expressed at different phases of the replication cycle in EBV-transformed B-cells (LCLs) which spontaneously reactivate lytic cycle. Selective shRNA-mediated knockdown of BNLF2a expression led to more efficient recognition of immediate-early (IE)- and early (E)-derived epitopes by CD8+ T cells, while knock down of BILF1 increased recognition of epitopes from E and late (L)-expressed antigens. Contrary to what might have been predicted from previous ectopic expression studies in EBV-negative model cell lines, the shRNA-mediated inhibition of BGLF5 expression in LCLs showed only modest, if any, increase in recognition of epitopes expressed in any phase of lytic cycle. These data indicate that whilst BNLF2a interferes with antigen presentation with diminishing efficiency as lytic cycle progresses (IE>E>>L), interference by BILF1 increases with progression through lytic cycle (IE<E<<L). Moreover, double-knockdown experiments showed that BILF1 and BNLF2a co-operate to further inhibit antigen presentation of L epitopes. Together, these data firstly indicate which potential immune-evasion functions are actually relevant in the context of lytic virus replication, and secondly identify lytic-cycle phase-specific effects that provide mechanistic insight into the immunodominance pattern seen for CD8+ T cell responses to EBV lytic antigens.
Highlights
Members of the human herpes family of viruses have co-evolved with their hosts to persist as largely asymptomatic, latent infections
Evasion of this immune-response is presumed to be due in part to immune-modulating mechanisms of certain Epstein-Barr virus (EBV)-encoded proteins expressed during lytic cycle replication
In this study we investigated these proteins in the context of EBV-infected cells in lytic cycle, and their functional recognition by EBV virus-specific CD8+ T-cells
Summary
Members of the human herpes family of viruses have co-evolved with their hosts to persist as largely asymptomatic, latent infections. Under conditions of immune T cell impairment as seen for example in immunosuppressed transplant recipients, herpesviruses may reactivate, often with clinical symptoms [1,2,3,4] This reflects the vital role of T cell-mediated immune responses in controlling, albeit not eliminating, persistent herpesvirus infections [5,6,7,8]. The ability of these viruses to persist and be transmitted by the immune host is achieved through two strategies: firstly, the establishment of a latent infection with minimal if any viral antigen expression in long lived cell types, and secondly, the synthesis of viral proteins that interfere with antigen processing pathways in the infected cell during the virusproductive phase of replication. Whether the c-herpesvirus immune evasion mechanisms cooperate with each other is unknown
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