Association analysis between HLA evolutionary divergence and CMV serological status in a cohort of 526 adult subjects

HLA Evolutionary Divergence (HED) measures the structural differences between alleles at a single locus reflecting the immunopeptidome. While high HED is associated with better T-cell responses against pathogens and tumors, its role in determining initial susceptibility to Cytomegalovirus (CMV) remains unexplored. We analyzed HLA typing and CMV IgG data from 526 adult HSCT patients and their donors at the ASST Grande Ospedale Metropolitano Niguarda (1987-2023). HED was calculated using the Grantham distance for HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1. We compared HED scores between CMV-seropositive (IgG+) and seronegative (IgG-) individuals using the Mann-Whitney U test to determine if HLA divergence influences initial viral susceptibility. The results showed no statistically significant differences across individual loci or grouped Class I and II HED scores, indicating no correlation between HED and CMV serological status. The lack of correlation with serostatus does not rule out HED's clinical utility. Given that HLA-specific binding to ppo5 and IEl is vital for viral control, future research should investigate if HED affects CMV reactivation posttransplant. Expanding this analysis to larger, multicenter datasets will help determine if HLA divergence serves as a viable prognostic marker for HSCT outcomes.