HOST-CELL-DETERMINED METHYLATION OF SPECIFIC EPSTEIN-BARR-VIRUS PROMOTERS REGULATES THE CHOICE BETWEEN DISTINCT VIRAL LATENCY PROGRAMS

Epstein-Barr virus (EBV) is capable of adopting three distinct forms o f latency: the type III latency program, in which six EBV-encoded nucl ear antigens (EBNAs) are expressed, and the type I and type II latency programs, in which only a single viral nuclear protein, EBNA1, is pro duced. Several groups have reported heavy CpG methylation of the EBV g enome in Burkitt's lymphoma cell lines which maintain type I latency, and loss of viral genome methylation in tumor cell lines has been corr elated with a switch to type III latency, Here, evidence that the type III latency program must be inactivated by methylation to allow EBV t o enter the type I or type II restricted latency program is provided, The data demonstrates that the EBNA1 gene promoter, Qp, active in type s I and II latency, is encompassed by a CpG island which is protected from methylation. CpG methylation inactivates the type III latency pro gram and consequently allows the type I or II latency program to opera te by alleviating EBNA1-mediated repression of Qp, methylation of the type III latency EBNA gene promoter, Cp, appears to be essential to pr event type III latency, since EBNA1 is expressed in all latently infec ted cells and, as shown here, is the only viral antigen required for a ctivation of Cp, EBV is thus a pathogen which subverts host-cell-deter mined methylation to regulate distinct genetic programs.