PT  - JOURNAL ARTICLE
AU  - Charles Hall
AU  - Vishal Koparde
AU  - Max Jameson-Lee
AU  - Abdelrhman Elnasseh
AU  - Allison Scalora
AU  - Jared Kobulnicky
AU  - Myrna Serrano
AU  - Catherine Roberts
AU  - Gregory Buck
AU  - Micheal Neale
AU  - Daniel Nixon
AU  - Amir Toor
TI  - Cytomegalovirus Antigenic Mimicry of Human Alloreactive Peptides: A Potential Trigger for Graft versus Host Disease
AID  - 10.1101/066571
DP  - 2016 Jan 01
TA  - bioRxiv
PG  - 066571
4099  - http://biorxiv.org/content/early/2016/07/28/066571.short
4100  - http://biorxiv.org/content/early/2016/07/28/066571.full
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.