UL4015-23 peptide in congenital cytomegalovirus infection. HLA-E restricted cytomegalovirus UL40 peptide polymorphism may represent a risk factor following congenital infection

Background/Purpose Congenital cytomegalovirus (cCMV) immunopathogenesis is largely unknown and multifactorial due to the complex interactions among viral, maternal, placental, and child features. Polymorphism in HLA-E binding UL4015-23 peptide mimics HLA-E complexed peptides from certain HLA A, B, C and G alleles, which regulate cellular immune response mediated by Natural Killer cells (NK) and CD8+ T cells. The aim of the study was to compare UL4015-23 peptides distribution in cCMV and the counterpart human leucocyte antigen class I (HLA-I) peptides in healthy population to investigate risk factors and markers for cCMV disease. Methods In this retrospective 10-years study, ul40 gene were directly sequenced from 242 clinical samples from 199 cases of cCMV (166 children and 33 pregnant or breast feeding women). Distribution of HLA-E binding UL4015-23 peptides was analyzed and compared to those of HLA-I (A, B, C and G) observed in a cohort of 444 healthy individuals. Results Nineteen different HLA-E binding UL4015-23 peptides were found. Three of them (VMAPRTLLL, VMAPRTLIL, VMAPRTLVL) were found in 88.3 % of UL40 and 100% of HLA-I of healthy individuals. In contrast, remaining 15 UL4015-23 (10.7%) were not found in HLA-I. A significant different peptide distribution between UL4015-23 and overall HLA-I and HLA-C peptides was found (p=3.773871e-40, p=3.992536e-50, respectively). Conclusion Our findings suggest that mismatching between UL40 peptides and HLA-I-derived peptides of children and mothers might play a role in cCMV disease and it may account for differences in outcome, morbidity and sequelae.