Differential methylation of Epstein-Barr virus latency promoters facilitates viral persistence in healthy seropositive individuals

Epstein-Barr virus (EBV) establishes a life-long infection in humans, with distinct viral latency programs predominating during acute and chronic phas es of infection. Only a subset of the EBV latency-associated antigens prese nt during the acute phase of EBV infection are expressed in the latently in fected memory B cells that serve as the long-term EBV reservoir. Since the EBV immortalization program elicits a potent cellular immune response, down regulation of viral gene expression in the long-term latency reservoir is l ikely to facilitate evasion of the immune response and persistence of EBV i n the immunocompetent host. Tissue culture and tumor models of restricted E BV latency have consistently demonstrated a critical role for methylation o f the viral genome in maintaining the restricted pattern of latency-associa ted gene expression. Here we extend these observations to demonstrate that the EBV genomes in the memory B-cell reservoir are also heavily and discret ely methylated. This analysis reveals that methylation of the viral genome is a normal aspect of EBV infection in healthy immunocompetent individuals and is not restricted to the development of EBV-associated tumors. In addit ion, the pattern of methylation very likely accounts for the observed inhib ition of the EBV immortalization program and the establishment and maintena nce of a restricted latency program. Thus, EBV appears to be the first exam ple of a parasite that usurps the host cell-directed methylation system to regulate pathogen gene expression and thereby establish a chronic infection .