Prospective analysis of the primary immune response during naturally acquired Epstein-Barr virus infection in humans

Abstract

During a viral infection, in addition to CD8 T cells, other cells of the immune system, costimulatory signals and cytokines, play important roles in activating the immune system. Unfortunately, the activities of the immune system may injure tissue and result in immunopathological disease. Infectious mononucleosis (IM) is one such example in which an exaggerated immune response to primary Epstein-Barr virus (EBV) infection is thought to cause disease. Little is known as to why EBV exposure commonly causes acute IM in adults, but rarely in children, or why some adults asymptomatically seroconvert. One school of thought attributes disease to viral cytopathy while another suggests that development of disease is determined by the immune response to virus (i.e. CD8 lymphocytosis as a result of activated cross-reactive memory cells, which may increase in frequency with age). One limitation is that most studies relied on evaluating patients undergoing symptomatic disease. Using natural primary EBV infection in humans as a model, we showed that a prospective study allows for capture of a broad range of symptomatic and asymptomatic individuals. Lymphocyte expansion was associated with disease severity during IM and lymphocytosis was also associated with viremia. In reconciling the published data, we suggest that viral load in the blood may therefore drive NK and CD8 T cell expansion. Moreover, we used several markers (CD38, HLA-DR, and granzyme B) to determine if pre-existing memory CD8 T cells became activated during acute IM. We found that primary EBV infection resulted in bystander activation of pre-existing influenza-specific and cytomegalovirus-specific CD8 T cells. However, these cells did not generally expand and therefore, the CD8 lymphocytosis observed during acute EBV infection was composed largely of EBV-specific cells. Finally, in contrast to the mouse model of IM, in humans, primary EBV infection did not result in attrition of bystander influenza and cytomegalovirus memory CD8 T cells. These findings outline the significance of studying immunity in humans, because our results differed from what mouse studies would have predicted. These finding also illustrate the advantages of prospective studies for understanding pathogenesis including being able to observe a broader spectrum of disease expression. Finally, these results provide unique insight into the underlying immune response of primary EBV infection, and suggest potential strategies for controlling EBV-related disease such as targeting viral replication to control viral load and suppressing the immune response.