The Immune Response to Epstein–Barr Virus

Abstract

Epstein–Barr virus (EBV) is the best known and most widely studied herpesvirus because of its clinical and oncogenic importance. It is also widely utilized as an important general model for investigating the antiviral immune response in humans because of its ubiquity in human populations, the ease with which virus-infected cells can be maintained in vitro, and the strength of the T-cell response during primary as well as persistent infection. Early interest in the immune response to EBV revolved primarily around the seroepidemiology of the virus, particularly in relation to the EBV-associated diseases. These studies exploited immunofluorescence assays that quantitatively assessed the antibody responses to various serologically defined viral antigens including viral capsid antigen (VCA), membrane antigen (MA), and Epstein–Barr nuclear antigen (EBNA). The observation that atypical lymphocytes expressed during acute infectious mononucleosis (IM) are not virus-infected B-cells but lymphoblasts of thymic origin led to an early suspicion that a cellular response might be important in controlling EBV infection. The huge increase in CD8T-cell numbers during primary infection provided further evidence of a critical role for the cellular immune response. More direct evidence for a strong T-cell response to EBV was provided in the late 1970s by Moss et al. (1) with their observation that virus-induced transformation of B-cells from healthy virus carriers was inhibited by T-cells in vitro. This T-cell response is generally a classic virus-specific response [CD8 human leukocyte antigen (HLA) class I-restricted] (2), although EBV-specific CD4 class II–restricted cytotoxic T lymphocytes (CTLs) have also been described (3,4). Following these observations, considerable interest was directed toward defining the EBV antigens that are the targets for this potent T-cell response. Although the MAs were initially considered the