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

Background: Congenital cytomegalovirus immunopathogenesis is largely unknown and multifactorial due to the complex interactions between viral, maternal, placental, and child factors. Polymorphisms in the HLA-E binding UL40_15-23 peptide mimics HLA-E complexed peptides from certain HLA-A, -B, -C and -G alleles, which regulate the cellular immune response driven by natural killer-cells (NK) and CD8 + T cells. The aim of this study was to compare UL40_15-23 peptides distribution in congenital CMV and the counterpart HLA Class I peptides in a healthy cohort to investigate risk factors and markers for cCMV disease. In this 10-year retrospective study, the UL40 gene was directly sequenced from 242 clinical samples from 199 cases of congenital CMV (166 children and 33 pregnant or breast feeding women). Distribution of HLA-E binding UL40_15-23 peptides was analyzed and compared to those of HLA Class I observed in a cohort of 444 healthy individuals.

Results: Nineteen different HLA-E binding UL40_15-23 peptides were found. Three of them (VMAPRTLIL, VMAPRTLLL, VMAPRTLVL) were found in 88.3% of UL40 and 100% of HLA Class I of healthy individuals. In contrast, 15 of them (10.7%) were not found in HLA Class I. The VMAPRTLFL peptide was found in 1% of UL40 and all HLA-G alleles. Significant differences in peptide (VMAPRTLIL, VMAPRTLLL, VMAPRTLVL, other UL40_15-23 peptides, other HLA Class I peptides) distribution between UL40_15-23 from congenital CMV and HLA-A, -B, -C and -G from healthy individuals were found.

Conclusions: Our findings suggest that a mismatch between UL40_15-23 peptides and HLA Class I peptides between children and mothers might play a role in congenital CMV disease, and it may account for differences in outcome, morbidity and sequelae.