  The association between human cytomegalovirus (hCMV) reactivation and the
development of graft-versus-host-disease (GVHD) has been observed in stem cell
transplantation (SCT). Seventy seven SCT donor-recipient pairs (DRP) (HLA
matched unrelated donor (MUD), n=50; matched related donor (MRD), n=27)
underwent whole exome sequencing to identify single nucleotide polymorphisms
(SNPs) generating alloreactive peptide libraries for each DRP (9-mer
peptide-HLA complexes); Human CMV CROSS (Cross-Reactive Open Source Sequence)
Database was compiled from NCBI; HLA class I binding affinity for each DRPs HLA
was calculated by NetMHCpan 2.8 and hCMV- derived 9-mers algorithmically
compared to the alloreactive peptide-HLA complex libraries. Short consecutive
(6 or greater) amino acid (AA) sequence homology matching hCMV to recipient
peptides was considered for HLA-bound-peptide (IC50<500 nM) cross reactivity.
Of the 70,686 hCMV 9-mers contained within the hCMV CROSS database, 29,658.8
+/- 9038.5 were found to match MRD DRP alloreactive peptides and 52,910.2 +/-
16121.8 matched MUD DRP peptides (Student's T-test, p<0.001). In silico
analysis revealed multiple high affinity, immunogenic CMV-Human peptide matches
(IC50<500 nM) expressed in GVHD-affected tissue-specific manner (proteins
expressed at 10 RPKM or greater). hCMV+GVHD was found in 18 patients, 13
developing hCMV viremia before GVHD onset with a subset analysis of 7 instances
of hCMV viremia prior to acute GVHD onset (n=3), chronic GVHD (n=2) and acute +
chronic GVHD (n=2) indicating cross reactive peptide expression within affected
organs. We propose that based on our analysis and preliminary clinical
correlations that hCMV immune cross-reactivity may cause antigenic mimicry of
human alloreactive peptides triggering GVHD.
