Genomic variations in EBNA3C of EBV associate with posttransplant lymphoproliferative disorder
Eden M. Maloney, Vincent A. Busque, Sin Ting Hui, Jiaying Toh, Marcelo Fernandez-Vina, Sheri M. Krams, Carlos O. Esquivel, Olivia M. Martinez
Eden M. Maloney, Vincent A. Busque, Sin Ting Hui, Jiaying Toh, Marcelo Fernandez-Vina, Sheri M. Krams, Carlos O. Esquivel, Olivia M. Martinez
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Research Article Transplantation

Genomic variations in EBNA3C of EBV associate with posttransplant lymphoproliferative disorder

Abstract

Epstein-Barr Virus (EBV) is a ubiquitous virus linked to a variety of lymphoid and epithelial malignancies. In solid organ and hematopoietic stem cell transplant recipients, EBV is causally associated with posttransplant lymphoproliferative disorder (PTLD), a group of heterogeneous lymphoid diseases. EBV+ B cell lymphomas that develop in the context of PTLD are generally attributed to the immunosuppression required to promote graft survival, but little is known regarding the role of EBV genome diversity in the development of malignancy. We deep-sequenced the EBV genome from the peripheral blood of 18 solid organ transplant recipients, including 6 PTLD patients. Sequences from 6 EBV+ spontaneous lymphoblastoid B cell lines (SLCL) were similarly analyzed. The EBV genome from PTLD patients had a significantly greater number of variations than EBV from transplant recipients without PTLD. Importantly, there were 15 nonsynonymous variations, including 8 in the latent cycle gene EBNA3C that were associated with the development of PTLD. One of the nonsynonymous variations in EBNA3C is located within a previously defined T cell epitope. These findings suggest that variations in the EBV genome can contribute to the pathogenesis of PTLD.

Authors

Eden M. Maloney, Vincent A. Busque, Sin Ting Hui, Jiaying Toh, Marcelo Fernandez-Vina, Sheri M. Krams, Carlos O. Esquivel, Olivia M. Martinez

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Figure 7

PTLD-associated variations alter binding of predicted epitopes to HLA-A, -B, and -DR alleles.

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PTLD-associated variations alter binding of predicted epitopes to HLA-A,...
For each PTLD-associated variation, a 29–amino acid sequence from the EBVhi and EBVlo reference sequence, with the location of the variable amino acid at location 15, was used to predict peptides that bind to HLA-A, -B, and -DR alleles on NetMHC 4.0 Server and NetMHCII. Peptides were predicted to be strong binders (SB), weak binders (WB), or nonbinders (NB). (A–F and H–J) Shown are the binding affinity concentrations for peptides for which the PTLD-associated variation caused a change in binding from a strong binder to a weak binder (A, D, H), a weak binder to a strong binder (B, E, I), or a weak binder to nonbinder (C, F, J). (A–C) HLA-A predicted epitopes for which the PTLD-associated variation changed the binding from strong to weak (A); weak to no binding (B), reference versus PTLD peptides, P = 0.009; and weak to strong (C). (D–G) HLA-B predicted epitopes for which the PTLD-associated variation changed the binding from strong to weak (D), reference versus PTLD peptides, P = 0.006; weak to no binding (E), reference versus PTLD peptide, P < 0.0001; weak to strong (F), reference versus PTLD peptide, P = 0.02; strong to no binding (G), reference versus PTLD peptide, P = 0.05. (H–J) HLA-DR predicted epitopes for which the PTLD-associated variation changed the binding from strong to weak (H), reference versus PTLD peptide, P = 0.02; weak to no binding (I), reference versus PTLD peptide, P = 0.0005; weak to strong (J), reference versus PTLD peptide, P = 0.005. (A–J) Statistical significance between number of reference peptide and PTLD peptide binding affinities was determined using paired 2-tailed t test with P value. *P < 0.05, **P < 0.01, ****P < 0.0001.