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

Abstract

The ubiquitous Epstein-Barr virus (EBV) is related to the development of lymphoma and is also the etiological agent for infectious mononucleosis (IM). Sequence variations in the gene encoding LMP1 have been deeply studied in different pathologies and geographic regions. Controversial results propose the existence of tumor-related variants, while others argued in favor of a geographical distribution of these variants. Reports assessing EBV variants in IM were performed in adult patients who displayed multiple variant infections. In the present study, LMP1 variants in 15 pediatric patients with IM and 20 pediatric patients with EBV-associated lymphomas from Argentina were analyzed as representatives of benign and malignant infections in children, respectively. A 3-month follow-up study of LMP1 variants in peripheral blood cells and in oral secretions of patients with IM was performed. Moreover, an integrated linkage analysis was performed with variants of EBNA1 and the promoter region of BZLF1. Similar sequence polymorphisms were detected in both pathological conditions, IM and lymphoma, but these differ from those previously described in healthy donors from Argentina and Brazil. The results suggest that certain LMP1 polymorphisms, namely, the 30-bp deletion and high copy number of the 33-bp repeats, are associated with EBV-related pathologies, either benign or malignant, instead of just being tumor related. Additionally, this is the first study to describe the Alaskan variant in EBV-related lymphomas that previously was restricted to nasopharyngeal carcinomas from North America.

A novel recombinant variant of latent membrane protein 1 from Epstein Barr virus in Argentina denotes phylogeographical association

“…On the other hand, co-infection with several EBV variants was reported in adult patients with IM [46–48], probably given by a higher viral inoculum transmitted through kissing; however, in pediatric primary infection these co-infections are infrequent, as observed in our previous reports in other EBV genes [38,42,49] and by others [43,44]. Indeed, when studying chronic active EBV infection in children, Jin et al found a small proportion of co-infections but failed to do so in IM samples [44].…”

Epstein-Barr Virus Latent Membrane Protein 1 Genetic Variability in Peripheral Blood B Cells and Oropharyngeal Fluids

“…We and others have previously shown significant differences in sequence and in vitro functional properties between viruses propagated in vitro and those sequenced directly from peripheral blood or body fluids (e.g., HIV and human cytomegalovirus [HCMV] [16][17][18][19]). Moreover, sequencing of tumor-associated viruses may select EBV strains with enhanced transforming properties for analysis (20)(21)(22)(23)(24)(25)(26)(27).…”

“…It consists of a short amino-terminal cytoplasmic tail (amino acids [aa] 1 to 25), six transmembrane domains (aa 26 to 196), and a carboxyl-terminal tail (aa 197 to 386). The C terminus contains 3 functional domains (carboxyl-terminal activating regions 1, 2, and 3 [CTAR1, -2, and -3]) that interact with cellular proteins to activate a wide array of signaling pathways, including nuclear factor B (NF-B), and cell cycle-regulatory molecules (20,22,(40)(41)(42).…”

Epstein–Barr Virus Strain Variation

“…Since references given in a previous review (Jenkins and Farrell 1996), many groups have investigated the presence of the 30-bp deletion LMP1 in normal carriers (Correa et al 2004) or a variety of EBV-associated diseases (Cheung et al 1998;Hayashi et al 1998;Zhang et al 2002;Tai et al 2004;Jen et al 2005;Chang et al 2006;Zhao et al 2005;Correa et al 2007;See et al 2008;Lorenzetti et al 2012;Banko et al 2012;Giron et al 2013). A rarer 69-bp deletion in the C-terminus has also been studied (Hadhri-Guiga et al 2006); it was reported to have a reduced ability to activate the cell AP1 transcription factor (Larcher et al 2003).…”

“…There has been considerable interest in BZLF1 variants that might affect its function or expression (Lorenzetti et al 2012;Jin et al 2010;Imajoh et al 2012;Yang et al 2014). Although there are suggestions of variant sequence in Zp correlating with disease (Martini et al 2007;Lorenzetti et al 2014), further functional analysis would be required to substantiate this.…”