An exceptional viral MHC class I-like protein encoded by squirrel monkey cytomegalovirus

Virus-host interactions have contributed to the acquisition of host-derived genetic material by viral genomes, although the mechanisms underlying such events remain incompletely understood. Here, we identified the S9 protein of squirrel monkey cytomegalovirus ( Saimiriine herpesvirus 4 ; SBHV4) as a unique viral protein showing extensive similarity to mammalian major histocompatibility complex class I (MHC class I) molecules. SBHV4-S9 shared 60.6% amino acid identity across 86.3% of the full-length human HLA-A protein, representing the highest level of similarity between a viral protein and an MHC class I molecule identified in Virus-Host DB-based screening. Structural modeling demonstrated that SBHV4-S9 possesses an overall architecture highly similar to HLA-A, including the characteristic MHC class I domains. Comprehensive phylogenetic analyses of primate MHC class I-like genes, incorporating assessments of substitution saturation, potential recombination signals, and comparisons between complete sequences and non-peptide-binding regions, showed that SBHV4-S9 consistently clustered with Old World monkey MHC class I sequences, including those from the genus Cercopithecus . However, the complex evolutionary history of MHC class I genes prevented definitive identification of the donor lineage or acquisition mechanism. These findings identify SBHV4-S9 as an exceptional viral MHC class I-like protein and highlight the complexity of reconstructing ancient virus-host evolutionary events.