Sequence Analysis of the Epstein-Barr Virus (EBV) Latent Membrane Protein-1 Gene and Promoter Region: Identification of Four Variants Among Wild-Type EBV Isolates

Abstract

Sequence variations in the Epstein-Barr virus (EBV) encoded latent membrane protein-1 (LMP-1) gene have been described in a Chinese nasopharyngeal carcinoma-derived isolate (CAO), and in viral isolates from various EBV-associated tumors. It has been suggested that these genetic changes, which include loss of a Xho I restriction site (position 169425) and a C-terminal 30-base pair (bp) deletion (position 168287-168256), define EBV genotypes associated with increased tumorigenicity or with disease among particular geographic populations. To determine the frequency of LMP-1 variations in European wild-type virus isolates, we sequenced the LMP1 promoter and gene in EBV from lymphoblastoid cell lines from healthy carriers and patients without EBV-associated disease. Sequence changes were often present, and defined at least four main groups of viral isolates, which we designate Groups A through D. The widespread prevalence of LMP-1 sequence variations, particularly the Xho I polymorphism and the 30-bp deletion, indicate that they cannot be used as simple markers for oncogenic viruses related to particular forms of EBV-associated tumor. Several of the structural changes detected occur, however, at sites where they may affect transcription, translation, or function of LMP-1. Future in vitro studies should aim to establish the functional importance of variations at these sites.

Increasing incidence of Epstein‐Barr virus–related nasopharyngeal carcinoma in the United States

“…[44][45][46][47] Several different sequence variations have been detected in the oncogenic viral latent membrane protein 1 (LMP1) of EBV in NPC tumors 44,[48][49][50] ; however, there remains no strong evidence to suggest an increased risk associated with different EBV variants. 33,[49][50][51][52] In the current study, we found that differentiated nonkeratinizing NPC incidence was increasing among all sex and race groups, leading to speculation of an increased role of EBV in NPC in the United States. Exploratory analyses into SEER incidence trends of extranodal NK/T-cell lymphoma, a form of non-Hodgkin's lymphoma consistently associated with EBV, 53-67 demonstrated significant increases in this cancer type among both sexes over this time period, further supporting the possibility of an increasing role in EBV etiology in US malignancies (see Supporting Fig.…”

Epstein–Barr virus strains and variations: Geographic or disease‐specific variants?

“…The majority of reports regarding the 30 bp-deletion of LMP1 have shown that this variation is widely spread worldwide [Hu et al, 1991;Sandvej et al, 1997;Correa et al, 2004;See et al, 2008;Tiwawech et al, 2008;Bobek et al, 2010;da Costa et al, 2015] -Table II. A recent meta-analysis, evaluated the association of this variation with NPC development and showed an association of del-LMP1 variant with NPC development described that the association is only observed in Asiatic populations while no association is observed for European and North African countries [da Costa et al, 2015].…”

Activation of the JAK/STAT Pathway in Epstein Barr Virus+-Associated Posttransplant Lymphoproliferative Disease: Role of Interferon-γ

“…To establish whether delayed activation of STAT is also observed with variants of LMP1 other than the B95.8 form, BL41 clones expressing NGFR-LMP1 containing the Cterminus of LMP1 isolated from PTLD-derived SLCL were studied. The clones were named according to the LMP1 group nomenclature (18) but group C clones were derived from two different cell lines, MF4 and VB5, obtained from two different PTLD patients and are indicated as C(M) and C(V), respectively. STAT1 is only activated after 24 h of NGFR-LMP1 cross-linking, while no significant increase in p-Tyr STAT3 was detected at either 30 min or 24 h ( Figure 3B and C).…”