Journal of virology 2017 08 23() pii 10.1128/JVI.00382-17
Epstein-Barr virus (EBV) is typically acquired asymptomatically in childhood. By contrast, infection later in life often leads to infectious mononucleosis (IM), a febrile illness characterised by anti-EBV IgM antibody-positivity, high loads of circulating latently-infected B cells, and a marked lymphocytosis caused by hyper-expansion of EBV-specific CD8(+) T cells plus milder expansion of CD56(dim) NKG2A(+) KIR(-) NK cells. How the two situations compare is unclear due to the paucity of studies on clinically-silent infection. Here we describe five prospectively-studied asymptomatic infections identified in a sero-epidemiological survey of University entrants. In each case the key blood sample had high cell-associated viral loads without marked IM-like CD8 lymphocytosis or NK cell disturbance. Two of the highest viral load cases showed a coincident expansion of activated EBV-specific CD8(+) T cells but overall CD8(+) T cell numbers were either unaffected or only mildly increased. Two slightly lower load cases, which serology suggests may have been caught earlier in the course of infection, also showed no T or NK cell expansion at the time. Interestingly, in another higher load case where T and NK cell responses were undetectable in the primary infection bleed, EBV-specific T cell responses did not appear until several months later, by which time virus loads in the blood had already fallen. Thus some asymptomatic primary infections have very high circulating viral loads and a cell-mediated immune response that is qualitatively similar to IM but of lower magnitude. However, others may be quite different and ultimately could reveal novel mechanisms of host control.IMPORTANCE Epstein-Barr virus (EBV) is transmitted orally, replicates in the throat and then invades the B lymphocyte pool through a growth-transforming latent infection. While primary infection in childhood is usually asymptomatic, delayed infection is associated with infectious mononucleosis (IM), a febrile illness with high circulating viral loads and an exaggerated virus-induced immune response involving both CD8(+) T cells and natural-killer (NK) cells. Here we show that in five cases of asymptomatic infection, virus loads in the blood are as high as in acute IM whereas cell-mediated responses, even where they resemble IM in timing and quality, are never as exaggerated. We infer that IM symptoms arise as a consequence not of the virus infection per se, but of the hyper-activated immune response. Interestingly, there were idiosyncratic differences among asymptomatic cases in the relationship between viral load and response kinetics, emphasising how much there is still to learn about primary EBV infection.