Epstein-Barr virus sequence mutations cause human diseases Free

In this issue of Blood, Khine et al¹ attempt to understand how natural sequence variation and mutations of the Epstein-Barr virus (EBV) genome are related to its pathology. Most people in the world become infected with EBV in early childhood. There is usually no disease, but in some people EBV contributes to various types of lymphoma, autoimmune diseases, and specific types of carcinoma. B lymphocytes are the main targets for EBV but some epithelial cells in the oropharynx are also infected (because the virus is transmitted through saliva).

Previous studies have already summarized some of the connections of EBV sequence variation to its pathology,² but Khine et al have analyzed a substantially large number of 990 EBV sequences (671 available in GenBank and 319 new EBV sequences), to give a more comprehensive overview of EBV variation.¹ The double-stranded DNA genome of the virus is about 172 kb in length and contains nearly 100 genes; the sequence is known to vary slightly in different world populations, perhaps reflecting differences in major histocompatability complex (MHC) and other geographic factors. The large number of sequences studied shows evidence for occasional recombination between EBV strains^1,3 and convergent mutations in small regions that are consistent with immune selection pressures. Notable examples of this, verified by peptide MHC loading assays,¹ are in EBNA3A, EBNA3B, and LMP1.

EBV contains many genes capable of regulating cell proliferation, preventing apoptosis and allowing immune evasion; these have evolved to allow the virus to persist for the life in the infected person in its latent infection cycle and avoid elimination by the immune system.⁴ Mutation or deletion of some of these genes (causing loss of function) can contribute to some types of blood cancer. The viral EBNA3B protein usually favors expression of the cell RB1 and PTEN tumor suppressor genes but about half of EBV-positive diffuse large B-cell lymphoma cases have EBV with a deletion of part of the EBNA3B gene^1,5 in the cancer cells. Other examples of viral sequence changes being involved in blood diseases are the frequent deletions of parts of the BamHI-A rightward transcript (BART) region of EBV in chronic active EBV disease and diffuse large B-cell lymphomas, clearly confirmed in this analysis.¹ The BART region produces a long nuclear RNA transcript that is spliced to release about 20 different microRNAs; these can regulate various aspects of the host cell biology, including cell proliferation and immune evasion.

The 990 EBV sequences analyzed were derived from many different parts of the world and small but characteristic geographic variations in the virus sequence are well defined.^1,6 For Burkitt lymphoma in sub-Saharan Africa and other parts of the world where malaria is endemic and for EBV-associated gastric cancer, the EBV seems to be largely typical of the endemic virus in those regions. In contrast, studies on the EBV in nasopharyngeal carcinoma (which has an unusually high incidence in southern China) have identified small sequence changes in the EBV EBER2 functional RNA that are frequent in nasopharyngeal carcinoma cases and are likely to contribute to the cancer.^7,8 

Improved understanding of viral genetic variation will have implications for diagnostics, early detection of disease risk and immunizing people against EBV diseases. The link between delayed primary EBV infection and later development of multiple sclerosis⁹ has stimulated several EBV vaccine projects, which are currently in early-stage trials. Although some of the links between EBV variation and disease had been proposed previously, the comprehensive and sophisticated analysis provided in this new study by Khine et al¹ provides a better description and a stronger basis for clinical and diagnostic implementation.

Conflict-of-interest disclosure: P.J.F. declares no competing financial interests.