UL40 human cytomegalovirus variability evolution patterns over time in renal transplant recipients.

Background. Human cytomegalovirus (HCMV) is the most common opportunistic pathogen infecting immunocompromised patients after transplantation. Although its immunomodulatory capacities and genomic variability participate in immune system evasion, they are poorly studied in clinical strains without culture amplification. One of HCMV immunomodulatory genes, UL40, confers HCMV-infected cells' protection from natural killer-mediated lysis through its encoded nonapeptide presented in the context of human leukocyte antigen-E. Methods. In three renal transplant recipients with different HCMV serostatus, we aimed to evidence the co-evolution of mixtures of HCMV variants over time with sequencing and cloning of HCMV UL40 gene. Results. Six months after renal transplantation in patient 1Bx, D+/R+, UL40 phylogenetic and bootscan analysis suggested the emergence of a recombination between two previous viral strains. In patient 8Bx, initially D+/R-, distribution of variants in five samples over 43 months was notably stable, with no visible emerging variants despite two renal engraftments and extended episodes of active infection. In patient 9Bx, also D+/R-, phylogenetic tree of viral variants revealed in the first sample a minor clone, confirmed by a specific polymerase chain reaction, related to the three subsequent dominant clones. Conclusions. In three HCMV-infected renal transplant recipients, we have evidenced different viral evolutive poly-morphisms including point mutations, recombination, and occasionally suggesting the intervention of several HCMV strains or a quasispecies-like distribution. This variability could contribute to viral adaptability in pathogenesis.