Methylation of the Epstein-Barr virus genome in normal lymphocytes

Epstein-Barr virus (EBV) latent infection in B cells persists over years or decades despite a sustained cytotoxic immune response to viral antigens. We present data that methylated EBV DNA can be detected in the normal lymphocytes of healthy volunteers. Whereas methylation of foreign DNA has been recognized as a potential cellular defense mechanism, methylation of EBV DNA may be an essential part of the virus life cycle in vivo, explaining the persistence of virus-infected B cells in the face of immune surveillance. Methylation of the C promoter helps to prevent expression of the immunodominant antigens expressed from this promoter. First recognized in tumors, methylation-associated evasion of immune surveillance is not an aberration restricted to tumor tissue but is detected in normal EBV-infected lymphocytes. Methylation of the viral genome in latency also provides an explanation for the CpG suppression associated with EBV but not other large DNA viruses.