Sequence variations in EBNA-1 may dictate restriction of tissue distribution of Epstein-Barr virus in normal and tumour cells.

Abstract

In seropositive individuals Epstein-Barr virus (EBV) establishes a virus reservoir in peripheral blood lymphocytes (PBLs). Transmission from one individual to another occurs via saliva due to a lytic (virion productive) phase of infection in the oropharynx. EBNA-1 is responsible for maintaining viral episomes in the host cell and could, therefore, also affect the persistence of the virus in different cell lineages. Based on sequence analysis of EBNA-1 we now demonstrate that (i) in addition to the prototype EBNA-1 (identical to the B95.8 virus EBNA-1), EBV in normal individuals encompasses multiple EBNA-1 subtypes, both in PBLs and in oral

The major immunogenic epitopes of Epstein-Barr virus (EBV) nuclear antigen 1 are encoded by sequence domains which vary among nasopharyngeal carcinoma biopsies and EBV-associated cell lines.

“…EBNA-1 is a phosphoprotein and some of the changes within NPC EBNA-1 could contribute to the change of phosphorylation pattern, such as aa 502 (Thr Asn) and aa 524 (Thr Ile), aa 585 (Thr Ile). Bhatia et al (1996) and Gutie! rrez et al (1997) then analysed EBNA-1 sequences within normal peripheral blood, BL and NPC biopsies from Hong Kong and France.…”

“…Previously, several studies documented sequence variation within the functionally important C terminus of EBNA-1, although no functional difference has yet been identified (Bhatia et al, 1996 ;Gutie! rrez et al, 1997 ;Wrightham et al, 1995 ;Snudden et al, 1995).…”

Diversity of naturally occurring Epstein-Barr virus revealed by nucleotide sequence polymorphism in hypervariable domains in the BamHI K and N subgenomic regions.

“…Potentially, these would allow variants to be discriminated even more finely. Hypervariability has thus been identified in the following regions : the C-terminal domain of the EBNA-1 ORF in the BamHI K region (Wrightham et al, 1995 ;Snudden et al, 1995 ;Bhatia et al, 1996 ;Gutie! rrez et al, 1997) ; the EBNA-2 gene, which is located in the BamHI WYH region (Aitken et al, 1994) ; several domains in the BamHI N region, including the LMP-1 gene (Miller et al, 1994), the N terminus of the LMP-2A gene (Busson et al, 1995), and an approximately 300 bp region upstream of the LMP-1 start codon (Hu et al, 1991) ; and the BZLF-1 gene (Packham et al, 1993).…”

Epstein-Barr Virus Nuclear Antigen (EBNA)-1 Carboxy-Terminal and EBNA-4 Sequence Polymorphisms in Nasal Natural Killer/T-Cell Lymphoma in the United States

“…The hypothesis that certain strains of EBV are associated with malignant transformation or with certain tumor types has been an area of active investigation. EBV gene polymorphisms have been demonstrated in a variety of EBV-associated tumors, including endemic Burkitt's lymphoma, Hodgkin's disease, immune deficiency-related lymphomas, gastric carcinoma, and nasopharyngeal carcinoma, as well as in EBV-positive reactive tissues and cultured lymphoblastoid cell lines (Bhatia et al, 1996;Chang et al, 1999;Chen et al, 1998;Fassone et al, 2000;Greiner et al, 2000;Gutierrez et al, 1997;Habeshaw et al, 1999;MacKenzie et al, 1999;Sandvej et al, 2000;Wrightham et al, 1995). Although some earlier studies suggested association of particular EBV strains with certain malignancies (Bhatia et al, 1996;Gutierrez et al, 1997), many subsequent studies have not confirmed this and, instead, have concluded that EBV sequence differences reflect geographic variations rather than any oncogenic potential Chen et al, 1998;Fassone et al, 2000;Habeshaw et al, 1999;MacKenzie et al, 1999;Sandvej et al, 2000).…”

“…Sequence analysis studies of EBNA-1 have focused on the C-terminal region, which contains a probable DNA binding-dimerization domain at residues 467-583 (Ambinder et al, 1991). Variations in EBNA-1 C-terminus have been classified according to the schema of Bhatia and colleagues relative to the prototype B95.8 virus, termed P-ala because of the presence of alanine at codon 487 (Bhatia et al, 1996;Gutierrez et al, 1997). The other prototype (P-thr) has a similar sequence but with threonine at 487.…”