Epstein-Barr virus LMP-1 natural sequence variants differ in their potential to activate cellular signaling pathways

The latent membrane protein 1 (LMP-1) oncogene of Epstein-Barr virus (EBV) is believed to contribute to the development of many EBV-associated tumors, and there is evidence that sequence variation can affect some functions of LMP-1. Most studies have been restricted to the prototype B95.8 LMP-1 gene and genes isolated from EBV of nasopharyngeal carcinoma (NPC) patients. He re, we analyzed the signaling functions of LMP-1 from a panel of nine EBV i solates, including representatives of four defined groups of European LMP-1 variants (groups A to D [K. Sandvej, J. W. Gratama, M. Munch, X. G. Zhou, R. L. Bolhuis, B. S. Andresen, N. Gregersen, and S. Hamilton-Dutoit, Blood 90:323-330, 1997]) and Chinese NPC-derived LMP-1. Chinese and group D varia nts activated the transcription factor NF-kappaB two- to threefold more eff iciently than B95.8 LMP-1, while Chinese, group B, and group D variants sim ilarly activated activator protein 1 (AP-1) transcription more efficiently than did B95.8 LMP-1. However, there were no amino acid substitutions in th e core binding regions for tumor necrosis factor receptor-associated adapte r proteins known to mediate NF-kappaB and AP-1 activation. In contrast, des pite sequence variation in the proposed Janus kinase 3 binding region, STAT activation was remarkably constant among the panel of LMP-1 variants. Anal ysis of the induction of CD54 (intercellular adhesion molecule 1) protein e xpression by the LMP-1 variants showed differences that did not correlate w ith either NF-kappaB or AP-1. Therefore, while the defined sequence variant groups do correlate with LMP-1 function, the results highlight the fact th at the relationship between sequence variation and signaling function is ex tremely complex. It appears unlikely that one particular amino acid substit ution or deletion will define a disease-associated variant of LMP-1.