C-terminal region of ebna-2 determines the superior transforming ability of type 1 epstein-barr virus by enhanced gene regulation of LMP-1 and CXCR7

Type 1 epstein-barr virus (ebv) strains immortalize b lymphocytes in vitro much more efficiently than type 2 ebv,a difference previously mapped to the ebna-2 locus. here we demonstrate that the greater transforming activity of type 1 ebv correlates with a stronger and more rapid induction of the viral oncogene lmp-1 and the cell gene cxcr7 (which are both required for proliferation of ebv-lcls) during infection of primary b cells with recombinant viruses. surprisingly,although the major sequence differences between type 1 and type 2 ebna-2 lie in n-terminal parts of the protein,the superior ability of type 1 ebna-2 to induce proliferation of ebv-infected lymphoblasts is mostly determined by the c-terminus of ebna-2. substitution of the c-terminus of type 1 ebna-2 into the type 2 protein is sufficient to confer a type 1 growth phenotype and type 1 expression levels of lmp-1 and cxcr7 in an ereb2.5 cell growth assay. within this region,the rg,cr7 and tad domains are the minimum type 1 sequences required. sequencing the c-terminus of ebna-2 from additional ebv isolates showed high sequence identity within type 1 isolates or within type 2 isolates,indicating that the functional differences mapped are typical of ebv type sequences. the results indicate that the c-terminus of ebna-2 accounts for the greater ability of type 1 ebv to promote b cell proliferation,through mechanisms that include higher induction of genes (lmp-1 and cxcr7) required for proliferation and survival of ebv-lcls. © 2011 cancian et al.