Human herpesvirus diversity is altered in predicted HLA class I binding peptides

Abstract

Abstract Human Leukocyte Antigen (HLA) Class I molecules present intracellularly derived peptide fragments for discrimination of self from non-self, thereby alerting the adaptive immune response to infecting pathogens. Among these pathogens are herpesviruses, including Epstein-Barr virus (EBV), which are large DNA viruses that have coevolved with humans. Previous analyses suggest that natural selection pressures imposed by HLA recognition may affect herpesvirus genetic diversity, especially for proteins involved in the establishment of latency. Because HLA allele frequencies are highly differentiated across human populations, we tested the hypothesis that herpesvirus latency genes have also become differentiated across human populations through adaptation to the local HLA environment. We predicted the protein regions most likely to be recognized by HLA in EBV, Human cytomegalovirus (HCMV), and Varicella-zoster virus (VZV) strains from >15 representative human populations. We compared sequence diversity and population differentiation in HLA-binding and non-binding regions of lytic and latent herpesvirus proteins. We observed increased population differentiation in herpesvirus latent proteins, specifically in regions targeted by HLA. Whereas HLA recognizes conserved peptides in most viral proteins, this pattern was reversed in HLA binding sites of EBV and HCMV proteins expressed in latency. We also predicted fewer HLA-binding latent EBV peptides from higher frequency HLA alleles, consistent with EBV adapting away from HLA recognition. Together, these results suggest that EBV and HCMV diversity is altered in regions recognized by HLA, perhaps due to population-specific natural selection by local HLA alleles.