Jayasooriya, Shamanthi, de Silva, Thushan I, Njie-jobe, Jainaba, Sanyang, Chilel, Leese, Alison M, Bell, Andrew I, McAulay, Karen A, Yanchun, Peng, Long, Heather M, Dong, Tao, Whittle, Hilton C, Rickinson, Alan B, Rowland-Jones, Sarah L, Hislop, Andrew D, and Flanagan, Katie L
Epstein-Barr virus (EBV) infection often occurs in early childhood and is asymptomatic. However, if delayed until adolescence, primary infection may manifest as acute infectious mononucleosis (AIM), a febrile illness characterised by global CD8+ T-cell lymphocytosis, much of it reflecting a huge expansion of activated EBV-specific CD8+ T-cells. While the events of AIM have been intensely studied, little is known about how these relate to asymptomatic primary infection. Here Gambian children (14–18 months old, an age at which many acquire the virus) were followed for the ensuing six months, monitoring circulating EBV loads, antibody status against virus capsid antigen (VCA) and both total and virus-specific CD8+ T-cell numbers. Many children were IgG anti-VCA-positive and, though no longer IgM-positive, still retained high virus loads comparable to AIM patients and had detectable EBV-specific T-cells, some still expressing activation markers. Virus loads and the frequency/activation status of specific T-cells decreased over time, consistent with resolution of a relatively recent primary infection. Six children with similarly high EBV loads were IgM anti-VCA-positive, indicating very recent infection. In three of these donors with HLA types allowing MHC-tetramer analysis, highly activated EBV-specific T-cells were detectable in the blood with one individual epitope response reaching 15% of all CD8+ T-cells. That response was culled and the cells lost activation markers over time, just as seen in AIM. However, unlike AIM, these events occurred without marked expansion of total CD8+ numbers. Thus asymptomatic EBV infection in children elicits a virus-specific CD8+ T-cell response that can control the infection without over-expansion; conversely, in AIM it appears the CD8 over-expansion, rather than virus load per se, is the cause of disease symptoms., Author Summary Primary infection with EBV, a common human herpesvirus, is typically asymptomatic in childhood but, if occurring in adolescence or later, often presents as AIM. This febrile illness is characterised by high virus loads in the blood and an exaggerated EBV-specific CD8+ T-cell response that pushes total CD8+ T-cell numbers well above normal levels. By contrast, very little is known about the events of asymptomatic primary infection. We therefore studied young Gambian children at an age at which many acquire EBV, monitoring them over six months for evidence of EBV infection by virus load in the blood, virus-specific IgM and IgG antibody status, and virus-specific CD8+ T-cell responses. Focusing on IgM-positive children with very recent EBV infection but no history of symptoms, we found that they carried a virus load equivalent to that seen in AIM patients and also mounted a classical virus-specific CD8+ T-cell response. However, that response, though it could occupy at least 15% of the circulating CD8+ T-cell pool, occurred without the huge global expansion of CD8 numbers seen in AIM. This work reinforces the idea that the host’s exaggerated CD8+ T-cell response, rather than the virus load per se, leads to the symptoms of AIM.