The extent of genetic diversity of Epstein-Barr virus and its geographic and disease patterns: A need for reappraisal

Epstein-Barr virus (EBV) is a ubiquitous, gamma-1 lymphotrophic virus etiologically linked to nasopharyngeal carcinoma (NPC), endemic to Southern China, and Burkitt lymphoma (BL), endemic to equatorial Africa, both of which are rare elsewhere in the world. Why EBV is associated with different malignancies in different geographic regions remains puzzling and may be related to EBV genotypic variability through specific disease and geographic associations. We review the literature on sequence variation in EBV genes, focusing on LMP-1, EBNA-1, and BZLF-1 and their distribution by geography and disease. Given the limitations of current studies, definitive conclusions regarding the link between EBV genotypes, disease and geography are not possible. We suggest that the true extent of EBV diversity is likely to be greater than is currently recognized. Additional studies conducted in carefully selected populations, that are sufficiently powered to provide robust estimates, and that utilize testing approaches that permit full characterization of viral diversity are needed to further our understanding of patterns of EBV genetic variation and their association with malignancies in different regions.