Identification of a Genetic Variation in ERAP1 Aminopeptidase that Prevents Human Cytomegalovirus miR-UL112-5p-Mediated Immunoevasion.

Herein, we demonstrate that HCMV miR-UL112-5p targets ERAP1, thereby inhibiting the processing and presentation of the HCMV pp65 495-503 peptide to specific CTLs. In addition, we show that the rs17481334 G variant, naturally occurring in the ERAP1 3 0 UTR, preserves ERAP1 from miR-UL112-5p-mediated degradation. Specifically, HCMV miR-UL112-5p binds the 30UTR of ERAP1 A variant, but not the 30UTR of ERAP1 G variant, and, accordingly,ERAP1 expression is reduced both at RNA and pro-tein levels only in human fibroblasts homozygous for the A variant. Consistently, HCMV-infected GGfibroblasts were more efficient in trimming viralantigens and being lysed by HCMV-peptide-specificCTLs. Notably, a significantly decreased HCMVseropositivity was detected among GG individualssuffering from multiple sclerosis, a disease modelin which HCMV is negatively associated with adult-onset disorder. Overall, our results identify a resis-tance mechanism to HCMV miR-UL112-5p-basedimmune evasion strategy with potential implicationsfor individual susceptibility to infection and otherdiseases.