EBNA1 sequences in Argentinean pediatric acute and latent Epstein–Barr virus infection reflect circulation of novel South American variants

Abstract

Epstein-Barr virus (EBV) is related to the development of lymphomas and is also the etiological agent for infectious mononucleosis (IM). Sequence variation of the EBNA1 gene, consistently expressed in all EBV-positive cells, has been widely studied. Based on the amino acid at codon 487 five major EBNA1 variants have been described, two closely related prototypic variants (P-ala and P-thr) and three variant sequences (V-leu, V-val, and V-pro). Sub-variants were then further classified based on mutations other than the originally described. While several studies proposed associations with tumors and/or anatomical compartments, others argued in favor of a geographical distribution of these variants. In the present study, EBNA1 variants in 11 pediatric patients with IM and 19 pediatric EBV lymphomas from Argentina were compared as representatives of benign and malignant infection in children, respectively. A 3-month follow-up study of EBNA1 variants in peripheral blood cells and in oral secretions of patients with IM was performed. A new V-ala variant which includes five V-ala sub-variants and three new V-leu sub-variants was described. These data favor the geographical association hypothesis since no evidence for a preferential compartment distribution of EBNA1 variants and sub-variants was found. This is the first study to characterize EBNA1 variants in pediatric patients with infection mononucleosis worldwide.

Distinctive Epstein-Barr Virus Variants Associated with Benign and Malignant Pediatric Pathologies: LMP1 Sequence Characterization and Linkage with Other Viral Gene Polymorphisms

“…Although not statistically significant, probably due to the low number of patients included in addition to its low frequency, arrangement no. 10 turned out to be very interesting, given that it combined a series of genetic variations which were preferentially or exclusively detected in our country (24,25). In accordance with the present results, incomplete linkage has been previously reported for LMP1, EBNA1, and EBNA2 polymorphisms (15).…”

“…On the other hand, coinfection with two EBV variants was detected in a low proportion (3/15) of IM patients in different compartments at some time point during the study when other EBV genes were assessed (Table 3) (24,25). In certain samples, even though only one LMP1 variant was detected, two variants of EBNA1 or the promoter region of BZLF1 were identified.…”

“…Coinfecting variants are in boldface. The EBNA1 column describes variants in EBNA1 genes according to the variant signature amino acids alanine, threonine, and leucine in codon 487 as described previously (24). In EBNA1 variant nomenclature, P stands for prototype (i.e., being closely related to the B95.8 sequence).…”

“…In previous reports, the naturally occurring variations in the C-ter domain of EBNA1 and in the promoter region of the BZLF1 gene were assessed and characterized in a proportion of pediatric patients from this series (24,25). Gene variants characterized in IM cases during the whole follow-up period and in lymphoma patients are summarized in Table 3.…”

Genome-Wide Analysis of Wild-Type Epstein–Barr Virus Genomes Derived from Healthy Individuals of the 1000 Genomes Project

“…A number of studies have tried to relate genetic variability of EBV strains to the prevalence of these diseases or to broadly defined geographical regions. Such efforts have focused on sequencing genes that play important roles in essential viral processes, such as BZLF1 (Gutiérrez et al 2002; Martini et al 2007), EBNA-1 (Habeshaw et al 1999; Brennan et al 2010; Lorenzetti et al 2010; Wang, Liu, Xing et al 2010), EBNA-2 (Aitken et al 1994), EBNA-3A , -3B , and -3C (Görzer et al 2006), LMP-1 (Edwards et al 1999, 2004), and LMP-2a (Wang, Liu, Jia et al 2010). However, the few studies that have classified EBV strains using combinations of variants from more than one gene suggest that recombination does take place and that many variant combinations are possible, thus increasing the difficulty of typing EBV strains (Gutiérrez et al 2000; Chang et al 2009; Sawada et al 2011).…”