Do Epstein-Barr Virus Mutations and Natural Genome Sequence Variations Contribute to Disease?

Abstract

Most of the world's population is infected by the Epstein-Barr virus (EBV), but the incidence of the diseases associated with EBV infection differs greatly in different parts of the world. Many factors may determine those differences, but variation in the virus genome is likely to be a contributing factor for some of the diseases. Here, we describe the main forms of EBV genome sequence variation, and the mechanisms by which variations in the virus genome are likely to contribute to disease. EBV genome deletions or polymorphisms can also provide useful markers for monitoring disease. If some EBV strains prove to be more pathogenic than others, this suggests the possible value of immunising people against infection by those pathogenic strains.

Keywords: EBER; Epstein–Barr virus; lymphoma; nasopharyngeal carcinoma; vaccine.

Figure 1

Schematic showing EBV genome locations containing SNPs characteristics for geographic origins of EBV on a scale of the reference NC007605 EBV genome. Vertical bars represent genomic positions of SNPs or haplotypes that are geographic location-specific. Exact details of SNPs specific for each geographic location are given in Table S3 of [23], (details of Ind-Pak-Sri locations will be published elsewhere, but are available on request). PNG is Papua New Guinea; Ind-Pak-Sri is India, Pakistan, Sri Lanka.

Figure 2

Genomic locations of Daudi and P3HR1 BL deletions (blue boxes) that result in increased expression of the BHRF1 protein from the spliced mRNAs, which normally express the EBNA proteins. Black lines above the open reading frame map indicate the spliced transcripts produced by intact EBV genomes. The novel RNA splicing from the W2 exon near Wp to the BHRF1 coding exon in BL cells with this deletion [41] is shown as a dashed line (blue). Symbols * are BHRF1 miRNAs.

Figure 3

Incidence of the different combinations of EBER2 and Zp SNPs in Chinese EBV strains, comparing viruses from NPC disease with healthy controls. x-axis shows the different possible combinations of Zp and EBER SNPs, classified into either B95 (the sequence of the reference B95-8 western strain) or the Zp-V3 and EBER2-M81 SNPs described in the text. Chi squared test shows a highly significant increase (p = 1 × 10⁻²⁷) in NPC cases in people whose EBV contains both EBER2-M81 and Zp-V3 SNPs.