The EBV Immunoevasins vIL-10 and BNLF2a Protect Newly Infected B Cells from Immune Recognition and Elimination

Abstract

Lifelong persistence of Epstein-Barr virus (EBV) in infected hosts is mainly owed to the virus' pronounced abilities to evade immune responses of its human host. Active immune evasion mechanisms reduce the immunogenicity of infected cells and are known to be of major importance during lytic infection. The EBV genes BCRF1 and BNLF2a encode the viral homologue of IL-10 (vIL-10) and an inhibitor of the transporter associated with antigen processing (TAP), respectively. Both are known immunoevasins in EBV's lytic phase. Here we describe that BCRF1 and BNLF2a are functionally expressed instantly upon infection of primary B cells. Using EBV mutants deficient in BCRF1 and BNLF2a, we show that both factors contribute to evading EBV-specific immune responses during the earliest phase of infection. vIL-10 impairs NK cell mediated killing of infected B cells, interferes with CD4+ T-cell activity, and modulates cytokine responses, while BNLF2a reduces antigen presentation and recognition of newly infected cells by EBV-specific CD8+ T cells. Together, both factors significantly diminish the immunogenicity of EBV-infected cells during the initial, pre-latent phase of infection and may improve the establishment of a latent EBV infection in vivo.

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 + T cells

“…The mechanisms of regulation we identified in that context-that is, regulation of MHC II, lysosomal enzymes, and IL-12-are likely relevant in latency as well and may explain why EBNA-specific CD4 + T cells are generally impaired in recognizing LCLs (46). The present study focused on established latency, but because we observed a strong miRNA regulation of EBNA1 recognition by CD8 + T cells already on days 1, 2, and 3 after infection, the hypothesis that EBV miRNAs generally suppress CD8 + T-cell recognition already in the first days of infection during prelatency (13,22,47) deserves closer investigation in the future.…”

“…Cells were refed weekly. After 4 wk, the cultures were analyzed for viable cells in MTT assays as previously described (22).…”

“…Recently, BDLF3 was identified as an additional lytic-cycle protein that targets MHC molecules for degradation (20). BNLF2a is also expressed early after infection in the prelatent phase (13 for a recent review) and reduces CD8 + T-cell recognition in the first days of infection but does not impair T-cell recognition in established latency (21,22). It is unclear, though, how latently EBV-infected B cells escape elimination by T cells, in particular during the latency III program that is characterized by a considerable antigenic load and an activated state expected to increase the immunogenicity of B cells (23).…”

Epstein-Barr virus reactivation in critically ill immunocompetent patients

“…We hypothesize that EBV could be reactivated due to immune suppression as it has been suggested for CMV and HSV. [12] …”

“…[10,11] During reactivation, EBV produces an interleukin-10 (IL-10) homolog, which is able to disturb the immune response, particularly, the activity of natural killer (NK) and CD4+ T cells. [12] EBV also produces proteins that impair the production of cytokines such as interferon, mainly during the lytic phase. [13][14][15] EBV induces diverse immune modifications.…”