5'-CODING AND REGULATORY REGION SEQUENCE DIVERGENCE WITH CONSERVED FUNCTION OF THE EPSTEIN-BARR-VIRUS LMP2A HOMOLOG IN HERPESVIRUS PAPIO

B-lymphotropic herpesviruses naturally infecting Old World primates sh are biologic, epidemiologic, pathogenic, and molecular features with t he human pathogen Epstein-Barr virus (EBV). These related gammaherpesv iruses have colinear genomes with considerable nucleotide homology. Th e replicative cycle genes share a high degree of homology across speci es, whereas the transformation-associated EBV latent genes appear to b e much more divergent. For example, the EBV BamHI Nhet fragment, which encodes all or part of the EBV latent infection membrane proteins, cr oss-hybridizes poorly to DNA from nonhuman primate B-lymphotropic herp esviruses. A viral DNA fragment corresponding to this region of the EB V genome was isolated from the baboon B-lymphotropic herpesvirus, herp esvirus papio, and used to clone a herpesvirus papio cDNA correspondin g to EBV LMP2A. At least three tyrosine kinase interaction motifs are conserved despite significant amino acid divergence of the herpesvirus papio LMP2A first exon from the EBV homolog. Functionally, the herpes virus papio LMP2A is tyrosine phosphorylated and induces tyrosine phos phorylation of cell proteins similar to EBV LMP2A. The 12 hydrophobic LMP2 transmembrane domains are well conserved. Two CBP (J kappa) bindi ng sites important for EBNA-2-induced transactivation of the LMP2A pro moter are also present in the herpesvirus papio LMP2A promoter, and th e simian LMP2A promoter is also responsive to EBV EBNA-2-induced trans activation in human B cells. Thus, transcriptional regulation, splicin g, kinase interaction sites, and tyrosine phosphorylation of the LMP2A homologs have been conserved despite significant sequence heterogenei ty in the preterminal repeat regions of these human and nonhuman prima te EBVs. The conservation of the LMP2 gene, despite its apparent nones sential role for in vitro EBV infection, suggests an important role fo r LMP2A in vivo. The similarities between these human and simian B-lym photropic herpesviruses, and the LMP2 genes in particular, suggest tha t the function of LMP2 in vivo could be addressed by using recombinant LMP2A-mutant simian viruses and experimental infection of Old World p rimates.