A reliable Epstein-Barr Virus classification based on phylogenomic and population analyses

Abstract

The Epstein-Barr virus (EBV) infects more than 90% of the human population, playing a key role in the origin and progression of malignant and non-malignant diseases. Many attempts have been made to classify EBV according to clinical or epidemiological information; however, these classifications show frequent incongruences. For instance, they use a small subset of genes for sorting strains but fail to consider the enormous genomic variability and abundant recombinant regions present in the EBV genome. These could lead to diversity overestimation, alter the tree topology and misinterpret viral types when classified, therefore, a reliable EBV phylogenetic classification is needed to minimize recombination signals. Recombination events occur 2.5-times more often than mutation events, suggesting that recombination has a much stronger impact than mutation in EBV genomic diversity, detected within common ancestral node positions. The Hierarchical Bayesian Analysis of Population Structure (hierBAPS) resulted in the differentiation of 12 EBV populations showed seven monophyletic and five paraphyletic. The populations identified were related to geographic location, of which three populations (EBV-p1/Asia/GC, EBV-p2/Asia II/Tumors and EBV-p4/China/NPC) were related to tumor development. Therefore, we proposed a new consistent and non-simplistic EBV classification, beneficial in minimizing the recombination signal in the phylogeny reconstruction, investigating geography relationship and even infer associations to human diseases. These EBV classifications could also be useful in developing diagnostic applications or defining which strains need epidemiological surveillance.

Comprehensive Evolutionary Analysis of Complete Epstein–Barr Virus Genomes from Argentina and Other Geographies

“…In particular, an estimated 1.5 million European migrants arrived to the Americas along with the introduction of an estimated 7 million African slaves between the 15th and 18th centuries [ 32 ]. It is worth mentioning that having possible recombinant sequences removed from the alignment strengthens our observations, since recombinant genomes could distort the topology of the tree, as demonstrated by Zanella et al [ 33 ]. In this way, we produced a reliable phylogenetic reconstruction with the entire genome sequence and obtained similar results regarding geographic variants, as previously described [ 28 ].…”

Evolution and Genetic Diversity of Primate Cytomegaloviruses

“…Another notable difference among human herpesviruses is the degree of geographic structuring of viral populations. At one extreme stand VZV and EBV, which display a clear spatial distribution of genetic diversity [82][83][84][85]. For instance, VZV clades 1, 3, and 6 are mainly transmitted in Europe, North America, and Australia, whereas clade 2 is primarily Asian [83].…”

Overview of Epstein–Barr-Virus-Associated Gastric Cancer Correlated with Prognostic Classification and Development of Therapeutic Options

“…EBV-2 predominates in Africa. With advances in genomic and bioinformatic technologies, the entire 175 kb EBV genome has been sequenced, producing evidence of vast EBV variations as the basis of numerous classification studies, e.g., [ 64 , 65 , 66 ]. Zanella and collaborators, though combined analysis of EBV genetic structural recombination with that of EBV phylogenetic mutations, proposed 12 distinct EBV phylopopulations (EBV-p) based on geographic location and tumor type [ 64 ].…”

“…Another study that focused specifically on EBV from non-Asian gastric cancer highlighted some shared mutations among gastric cancer samples independent of geographical origin. These shared mutations mapped to antigen epitopes, which suggests EBV immune evasion may be involved in the development of EBVaGC [ 65 ]. In recent years, a higher prevalence of EBVaGC was evidenced in Latin America compared to Europe and Asia [ 66 , 67 ].…”

“…High MHC-II expression in EBVaGCs suggests that this tumor shows a more important role in antigen presentation than EBV-negative GC [ 65 ]. Nonetheless, although, EBVaGC recruits numerous reactive immune cells [ 114 ], specifically CD8+ T cells and macrophages [ 115 ], numerous strategies are used by EBV to evade the immune response.…”