Immunity & infection
EBV infection can induce acute infectious mononucleosis (AIM), with symptoms of mild to severe lymphadenopathy, sore throat, splenomegaly and prolonged fatigue. These symptoms are associated with a massive expansion of CD8+ T cells, which are mostly directed to two EBV immunodominant epitopes: BMLF1280 and BRLF1190 in HLA-A2:01+ patients. We have shown that during AIM the frequency of unique crossreactive CD8+ T cells between influenza A (IAV)-M158 and EBV-BMLF1 not only directly correlate with but predict disease severity. However, little is known about EBV-specific and crossreactive CD8 T cell responses in the vast majority of individuals, who asymptomatically seroconvert and become persistently infected. Here, we hypothesized that asymptomatic donors would have decreased EBV-specific and crossreactive CD8 T cell responses near the time of seroconversion as compared to AIM patients. By tracking seronegative donors at the time of college admission every 3-4 months for their 4 years in college we have identified 20 asymptomatic seroconverters who had surprisingly low or non-existent EBV lytic epitope specific responses in the first year after seroconversion with no evidence of cross-reactive IAV-M1/EBV-BMLF1 memory CD8 T cell activation ex vivo. In the presence of these much lower and delayed CD8 T cell responses, their viral loads were equivalent to AIM patients. There was also a great deal of individual variation in the kinetics of their CD8 T cell responses. These results are consistent with CD8 T cell activation mediating the symptomatology of AIM, and strongly suggest that in the asymptomatic donor EBV is silently infecting the host.