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

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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. Despite strong cellular and humoral immune responses, herpesviruses persist in their hosts for a lifetime. Epstein-Barr virus (EBV) is a herpesvirus that infects human B cells. This results in a latent infection where only a minimal set of viral proteins is expressed and infected cells cannot be eradicated by immune cells. When the virus reactivates in order to produce progeny, many viral proteins are expressed that are potential targets of immunity, but the virus coexpresses viral “immunoevasins” that blunt immune responses. Similarly, in the very first phase of B cell infection by EBV, called the pre-latent phase, a rather wide spectrum of antigens is expressed. However, it has been unknown whether viral immunoevasion occurs in this phase. Here we show that two viral immunoevasins are active in the pre-latent phase and prevent immune recognition by a variety of mechanisms: they reduce the presentation of EBV antigens to CD8+ killer T cells, prevent an attack by natural killer cells, and reduce the function of CD4+ helper T cells. Thus, it seems to be important for the virus to shield itself from attack by immune cells during the pre-latent stage.

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