Abstract

The Epstein-Barr virus (EBV) induces B-cell proliferation with high efficiency through expression of latent proteins and microRNAs. This process takes place in vivo soon after infection, presumably to expand the virus reservoir, but can also induce pathologies, e.g. an infectious mononucleosis (IM) syndrome after primary infection or a B-cell lymphoproliferation in immunosuppressed individuals. In this paper, we investigated the growth characteristics of EBV-infected B-cells isolated from transplant recipients or patients with IM. We found that these cells grew and withstood apoptosis at highly variable rates, suggesting that the expansion rate of the infected B-cells widely varies between individuals, thereby influencing the size of the B-cell reservoir and the ability to form tumors in infected individuals. All viruses investigated were type 1 and genetically close to western strains. EBV-infected B-cells expressed the transforming EBV latent genes and microRNAs (miRNAs) at variable levels. We found that the B-cell growth rates positively correlated with the BHRF1 miRNA levels. Comparative studies showed that infected B-cells derived from transplant recipients with iEBVL on average expressed higher levels of EBV miR-BHRF1 miRNAs and grew more rapidly than B-cells from IM patients, suggesting infection by more transforming viruses. Altogether, these findings suggest that EBV infection has a highly variable impact on the B-cell compartment that probably reflects the genetic diversity of both the virus and the host. It also demonstrates the unexpected finding that B-cells from different individuals can grow at different speed under the influence of the same virus infection.

Highlights

  • The Epstein-Barr virus (EBV) infects the large majority of the human population [1]

  • 1) Growth characteristics of a panel of EBV-positive B-cell lines established from transplant recipients and from patients with infectious mononucleosis (IM)

  • We investigated the growth characteristics of these cell lines under optimal cell concentration (3x105/ml) and medium supply, together with a panel of ten spontaneously proliferating EBV-infected B-cells (sLCLs) established from nine individuals with IM and one line from a patient with PTLD

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Summary

Introduction

The Epstein-Barr virus (EBV) infects the large majority of the human population [1]. The virus targets primary B-cells in which it induces an unlimited B-cell proliferation [3]. This process depends on the expression of the Epstein-Barr nuclear antigens (EBNA) and of the latent membrane proteins (LMP) subfamilies [3]. EBV MicroRNAs (miRNAs) have been found to modulate the transforming potential of the virus [4, 5]. Whilst the miRNAs clustered around the BHRF1 gene potentiate B-cell proliferation, those clustered in the BART transcripts have the opposite effect, probably through their action on LMP1 [6,7,8]

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