Epstein–Barr virus gene expression and latent membrane protein 1 gene polymorphism in pediatric liver transplant recipients

Abstract

Immunosuppressed pediatric transplant recipients are at risk of developing Epstein-Barr virus (EBV)-associated complications (such as post-transplant lymphoproliferative disorders). Monitoring of the EBV DNA level in blood alone has a low predictive value for the post-transplant course of EBV infection and its complications. Therefore, additional prognostic markers are widely sought. The study aim was to analyze EBV gene expression patterns and LMP1 polymorphism in relation to EBV DNA levels in pediatric liver transplant recipients. EBV load measurement, LMP1 variant, and gene expression analysis were performed in collected prospectively multiple blood samples from 30 patients. Several distinct patterns of EBV gene expression were identified: latency 2 (71%), latency 3 (13%), latency 0 (11%), and lytic infection (5%). In most children's multiple blood samples, both EBV gene expression patterns and expression levels of individual EBV genes varied significantly over time. EBV gene expression patterns were not associated with the EBV load. However, the viral load correlated with the LMP1 and LMP2 expression (r = 0.34; P = 0.006, and r = 0.45; P = 0.001, respectively). Two variants of the LMP1 gene were detected, and they were consistent over time in individual patients. A wild type of LMP1 was associated with higher EBV-DNA loads (P = 0.03). This indicates that EBV infection in immunosuppressed patients is a very dynamic process, but changes in the state of EBV infection do not influence significantly the viral load. The latter, however, can be associated with the activity of LMP1 and LMP2 genes, as well as polymorphism of LMP1.

Molecular Pathogenesis of B-Cell Posttransplant Lymphoproliferative Disorder: What Do We Know So Far?

“…The 30-bp deleted LMP1 variant has been associated with lower EBV serum levels compared to wild-type LMP1 [92]. Other studies have revealed differences in signaling properties of LMP1 variants that influence B-cell survival and proliferation [93].…”

The IPTA Nashville Consensus Conference on Post‐Transplant lymphoproliferative disorders after solid organ transplantation in children: III – Consensus guidelines for Epstein‐Barr virus load and other biomarker monitoring

“…No consistent peripheral blood EBV gene expression patterns have been found that clearly associated with quantitative EBV DNA measurement 98,102 or are predictive for, or diagnostic of, PTLD although only small numbers of PTLD patients have been studied 54,97,99,102 . Currently there is no clear additional benefit of EBV gene expression profiling over measurement of EBV DNAemia alone in SOT recipients.…”

“…45,54,99,102,103 Results have been variable, likely due to factors including nonstandardization of assays, use of pooled cells which precludes determination of specific expression patterns among individual cells, 6 populations studied 45,53,54,56,[97][98][99][100][101][102][103] and differences in study design. 53,54,[99][100][101][102] No consistent peripheral blood EBV gene expression patterns have been found that clearly associated with quantitative EBV DNA measurement 98,102 or are predictive for, or diagnostic of, PTLD although only small numbers of PTLD patients have been studied. 54,97,99,102 Currently there is no clear additional benefit of EBV gene expression profiling over measurement of EBV DNAemia alone in SOT recipients.…”

“…EBV gene expression of latent and lytic genes in blood has been investigated as alternative or adjunct biomarkers of PTLD risk or PTLD diagnosis in both SOT 53,54,56,[97][98][99][100][101][102] and HSCT patients. 45,54,99,102,103 Results have been variable, likely due to factors including nonstandardization of assays, use of pooled cells which precludes determination of specific expression patterns among individual cells, 6 populations studied 45,53,54,56,[97][98][99][100][101][102][103] and differences in study design. 53,54,[99][100][101][102] No consistent peripheral blood EBV gene expression patterns have been found that clearly associated with quantitative EBV DNA measurement 98,102 or are predictive for, or diagnostic of, PTLD although only small numbers of PTLD patients have been studied.…”

“…EBV gene expression of latent and lytic genes in blood has been investigated as alternative or adjunct biomarkers of PTLD risk or PTLD diagnosis in both SOT 53,54,56,[97][98][99][100][101][102] and HSCT patients. 45,54,99,102,103 Results have been variable, likely due to factors including nonstandardization of assays, use of pooled cells which precludes determination of specific expression patterns among individual cells, 6 populations studied 45,53,54,56,[97][98][99][100][101][102][103] and differences in study design.…”