Abstract
Epstein Barr Virus (EBV) infects more than 95% of the population whereupon it establishes a latent infection of B-cells that persists for life under immune control. Primary EBV infection can cause infectious mononucleosis (IM) and long-term viral carriage is associated with several malignancies and certain autoimmune diseases. Current efforts developing EBV prophylactic vaccination have focussed on neutralising antibodies. An alternative strategy, that could enhance the efficacy of such vaccines or be used alone, is to generate T-cell responses capable of recognising and eliminating newly EBV-infected cells before the virus initiates its growth transformation program. T-cell responses against the EBV structural proteins, brought into the newly infected cell by the incoming virion, are prime candidates for such responses. Here we show the structural EBV capsid proteins BcLF1, BDLF1 and BORF1 are frequent targets of T-cell responses in EBV infected people, identify new CD8+ and CD4+ T-cell epitopes and map their HLA restricting alleles. Using T-cell clones we demonstrate that CD4+ but not CD8+ T-cell clones specific for the capsid proteins can recognise newly EBV-infected B-cells and control B-cell outgrowth via cytotoxicity. Using MHC-II tetramers we show a CD4+ T-cell response to an epitope within the BORF1 capsid protein epitope is present during acute EBV infection and in long-term viral carriage. In common with other EBV-specific CD4+ T-cell responses the BORF1-specific CD4+ T-cells in IM patients expressed perforin and granzyme-B. Unexpectedly, perforin and granzyme-B expression was sustained over time even when the donor had entered the long-term infected state. These data further our understanding of EBV structural proteins as targets of T-cell responses and how CD4+ T-cell responses to EBV change from acute disease into convalescence. They also identify new targets for prophylactic EBV vaccine development.
Highlights
Epstein Barr Virus (EBV), a gammaherpes virus that primarily infects human B-cells and epithelial cells, infects over 95% of the world’s population
To characterise the total T-cell response to EBV structural proteins in an unbiased manner we constructed a panel of modified vaccina Ankara (MVA) viruses each expressing a single EBV gene: the capsid proteins BcLF1, BORF1, BDLF1, the tegument protein BNRF1 or the viral glycoprotein gp350
The frequency of response to BcLF1 was significantly higher compared to BORF1 and BNRF1 (p = 0.015, Friedman test with Dunn’s multiple comparison test)
Summary
Epstein Barr Virus (EBV), a gammaherpes virus that primarily infects human B-cells and epithelial cells, infects over 95% of the world’s population. IM patients have a highly expanded population of EBV-specific CD8+ T-cells accompanied by a smaller population of virus-specific CD4+ T-cells [2,3,4,5,6,7,8]. These T-cells target the large array of proteins expressed sequentially in the virus lytic cycle during replication, and the six nuclear antigens (EBNA1, 2, 3A, 3B, 3C and LP) and two latent membrane proteins (LMP1 and 2) that drive the life-long persistent infection EBV establishes in the host’s B-cell system [8]. Viral gene expression is down-regulated and these T-cells decrease in frequency, entering long-term memory where they are essential for controlling the periodic reactivations of EBV that occur in the oropharynx to produce infectious virus to infect new hosts [8]
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