5' Coding and regulatory region sequence divergence with conserved function of the Epstein-Barr virus LMP2A homolog in herpesvirus papio

Abstract

B-lymphotropic herpesviruses naturally infecting Old World primates share biologic, epidemiologic, pathogenic, and molecular features with the human pathogen Epstein-Barr virus (EBV). These related gammaherpesviruses have colinear genomes with considerable nucleotide homology. The replicative cycle genes share a high degree of homology across species, whereas the transformation-associated EBV latent genes appear to be much more divergent. For example, the EBV BamHI Nhet fragment, which encodes all or part of the EBV latent infection membrane proteins, cross-hybridizes poorly to DNA from nonhuman primate B-lymphotropic herpesviruses. A viral DNA fragment corresponding to this region of the EBV genome was isolated from the baboon B-lymphotropic herpesvirus, herpesvirus papio, and used to clone a herpesvirus papio cDNA corresponding 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 herpesvirus papio LMP2A is tyrosine phosphorylated and induces tyrosine phosphorylation of cell proteins similar to EBV LMP2A. The 12 hydrophobic LMP2 transmembrane domains are well conserved. Two CBP (Jk) binding sites important for EBNA-2-induced transactivation of the LMP2A promoter are also present in the herpesvirus papio LMP2A promoter, and the simian LMP2A promoter is also responsive to EBV EBNA-2-induced transactivation in human B cells. Thus, transcriptional regulation, splicing, kinase interaction sites, and tyrosine phosphorylation of the LMP2A homologs have been conserved despite significant sequences heterogeneity in the preterminal repeat regions of these human and nonhuman primate EBVs. The conservation of the LMP2 gene, despite its apparent nonessential role for in vitro EBV infection, suggests an important role for LMP2A in vivo. The similarities between these human and simian B-lymphotropic herpesviruses, and the LMP2 genes in particular, suggest that the function of LMP2 in vivo could be addressed by using recombinant LMP2A-mutant simian viruses and experimental infection of Old World primates.