Asymptomatic Primary Infection with Epstein-Barr Virus: Observations on Young Adult Cases

Abstract

Epstein-Barr virus (EBV) is typically acquired asymptomatically in childhood. In contrast, infection later in life often leads to infectious mononucleosis (IM), a febrile illness characterized by anti-EBV IgM antibody positivity, high loads of circulating latently infected B cells, and a marked lymphocytosis caused by hyperexpansion of EBV-specific CD8+ T cells plus a milder expansion of CD56dim NKG2A+ KIR− natural killer (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 patients with asymptomatic infections identified in a seroepidemiologic survey of university entrants. In each case, the key blood sample had high cell-associated viral loads without a marked CD8 lymphocytosis or NK cell disturbance like those seen in patients during the acute phase of IM. Two of the cases with the highest viral loads 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 cases with slightly lower loads, in whom serology suggests the infection may have been caught earlier in the course of infection, also showed no T or NK cell expansion at the time. Interestingly, in another case with a higher viral load, in which T and NK cell responses were undetectable in the primary blood sample in which infection was detected, EBV-specific T cell responses did not appear until several months later, by which time the viral loads in the blood had already fallen. Thus, some patients with asymptomatic primary infections have very high circulating viral loads similar to those in patients during the acute phase of IM and a cell-mediated immune response that is qualitatively similar to that in IM patients but of a lower magnitude. However, other patients may have quite different immune responses that 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 in which patients have 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, viral loads in the blood were as high as those in patients during the acute phase of IM, whereas the cell-mediated responses, even when they resembled those in patients during the acute phase of IM in timing and quality, were never as exaggerated. We infer that IM symptoms arise as a consequence not of the virus infection per se but of the hyperactivated immune response. Interestingly, there were idiosyncratic differences among asymptomatic cases in the relationship between the viral load and the response kinetics, emphasizing how much there is still to ...

High Levels of Epstein–Barr Virus Nuclear Antigen-1-Specific Antibodies and Infectious Mononucleosis Act Both Independently and Synergistically to Increase Multiple Sclerosis Risk

“…Both individuals with subclinical infection and IM display similarly high levels of viral load in the blood, and the fraction of EBV-infected memory B cells following subclinical infection is similar to that observed in IM (17,18). However, subclinical infection does not evoke a massive peripheral CD8+ T cell response, whereas the symptoms of IM are caused by the patient mounting an exaggerated cellular immune response (18). The outcome of primary EBV infection may be influenced by host genetics (19)(20)(21), an age-related impaired CD8+ T cell function (22)(23)(24), or changes in the CD8+ T cell repertoire in response to prior infections (25).…”

“…How past IM contributes to further increase MS risk is not clear. Both individuals with subclinical infection and IM display similarly high levels of viral load in the blood, and the fraction of EBV-infected memory B cells following subclinical infection is similar to that observed in IM (17,18). However, subclinical infection does not evoke a massive peripheral CD8+ T cell response, whereas the symptoms of IM are caused by the patient mounting an exaggerated cellular immune response (18).…”

Human γ-Herpesvirus Infection, Tumorigenesis, and Immune Control in Mice with Reconstituted Human Immune System Components

“…At this time point, total viral loads reach 10 7 viral DNA copies/g in secondary lymphoid tissues like spleen and lymph nodes. These viral loads are comparable to blood viral loads in patients with symptomatic primary EBV infection, called infectious mononucleosis (IM) ( 22 ) that surprisingly do not differ very much from overall blood viral loads of asymptomatic primary infection ( 23 , 24 ). In most of these studies, the B95-8 EBV strain was used, which reactivates only very weakly into lytic replication and was originally isolated from an American IM patient ( 25 , 26 ).…”

Recent Advances in Diagnostic Approaches for Epstein–Barr Virus

“…However, some patients with primary infection are negative for VCA IgM [49]. Meanwhile, anti-EBNA-2 IgG (EBNA-2 IgG) appears early, while anti-EBNA-1 IgG (EBNA-1 IgG) is typically not detectable during the initial three-to-four weeks following clinical symptoms and is therefore an indication of past infection [49][50][51]. In addition, EBNA-1 IgG is mostly negative in immunosuppressed patients and in patients with persistent infection, while IgM-VCA Abs appear early during infection and normally disappear within four-to-six weeks [46,49,52].…”