Mapping the landscape of host-pathogen coevolution: HLA class I binding and its relationship with evolutionary conservation in human and viral proteins Academic Article uri icon


  • Received 16 September 2010/Accepted 9 November 2010 The high diversity of HLA binding preferences has been driven by the sequence diversity of short segments of relevant pathogenic proteins presented by HLA molecules to the immune system. To identify possible commonalities in HLA binding preferences, we quantify these using a novel measure termed “targeting efficiency,” which captures the correlation between HLA-peptide binding affinities and the conservation of the targeted proteomic regions. Analysis of targeting efficiencies for 95 HLA class I alleles over thousands of human proteins and 52 human viruses indicates that HLA molecules preferentially target conserved regions in these proteomes, although the arboviral Flaviviridae are a notable exception where nonconserved regions are preferentially targeted by most alleles. HLA-A alleles and several HLA-B alleles that have maintained close sequence identity with chimpanzee homologues target conserved human proteins and DNA viruses such as Herpesviridae and Adenoviridae most efficiently, while all HLA-B alleles studied efficiently target RNA viruses. These patterns of host and pathogen specialization are both consistent with coevolutionary selection and functionally relevant in specific cases; for example, preferential HLA targeting of conserved proteomic regions is associated with improved outcomes in HIV infection and with protection against dengue hemorrhagic fever. Efficiency analysis provides a novel perspective on the coevolutionary relationship between HLA class I molecular diversity, self-derived peptides that shape T-cell immunity through ontogeny, and the broad range of viruses that subsequently engage with the adaptive immune response. Human leukocyte antigen (HLA) molecules and viruses are thought to be locked in an evolutionary arms race, where viruses adapt to evade HLA-restricted immune responses and HLA alleles evolve to optimize the fitness of human populations in the face of a wide range of pathogen species as well as the genetic variation within each pathogenic species. HLA diversity has been driven and maintained by heterozygote advantage (25), which is most evident in geographical regions with greater pathogen diversity (51), and by frequency-dependent selection, in which low-frequency allelic variants gain advantage in an environment of shifting pathogen selection (58). In turn, the selective pressures of HLA-restricted immune responses on pathogens are evident in a range of immune evasion strategies employed by viruses and encoded in

publication date

  • January 1, 2011