RT Journal Article
SR Electronic
T1 Cytomegalovirus Antigenic Mimicry of Human Alloreactive Peptides: A Potential Trigger for Graft versus Host Disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 066571
DO 10.1101/066571
A1 Charles Hall
A1 Vishal Koparde
A1 Max Jameson-Lee
A1 Abdelrhman Elnasseh
A1 Allison Scalora
A1 Jared Kobulnicky
A1 Myrna Serrano
A1 Catherine Roberts
A1 Gregory Buck
A1 Micheal Neale
A1 Daniel Nixon
A1 Amir Toor
YR 2016
UL http://biorxiv.org/content/early/2016/07/28/066571.abstract
AB 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) amino acid (AA) sequence homology matching hCMV to recipient peptides was considered for HLA-bound-peptide (IC50<500nM) 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). 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.