title: Quantifying how MHC polymorphism prevents pathogens from adapting to the antigen presentation pathway.
abstract: The classical antigen presentation pathway consists of two monomorphic (proteasome and TAP) and one polymorphic components (MHC Class I). Viruses can escape CTL responses by mutating an epitope so that it is no longer correctly processed by the pathway. Whereas escape mutations that affect MHC binding are typically no longer under selection pressure in the next host of the virus (as hosts differ in their MHC alleles), escape mutations that affect the antigen processing of epitope precursors prevent the use of those epitope precursors by any of the MHC alleles in a host population. Viruses might therefore be under selection pressure to adapt to the monomorphic proteasome and TAP. We designed an agent-based model of a host population, in which an HIV-1 like virus adapts to the antigen presentation pathway of individual hosts, as the virus spreads through the population. We studied how the polymorphism of the MHC and the monomorphism of the proteasome and TAP affected the level of adaptation to the host population that the virus could reach. We found that due to the polymorphism and high specificity of the MHC class I molecules, the CTL epitopes that are targeted by the CTL responses of different hosts do not share many epitope precursors. Therefore, escape mutations in epitope precursors are frequently released from immune selection pressure, and can revert back to the virus wildtype sequence. As a result, the selection pressure on the virus to adapt to the proteasome and TAP is relatively small, which explains the low level of adaptation of the virus to the monomorphic steps in the antigen presentation pathway.
authors.affiliation: RIVM, Bilthoven, The Netherlands; Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands. Electronic address: boris.schmid@gmail.com.
authors.forename: B V
authors.initials: BV
authors.lastname: Schmid
authors.affiliation: Academic Biomedical Centre, Utrecht, The Netherlands; Faculty of Biology, Utrecht University, Utrecht, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Kęsmir
authors.affiliation: Faculty of Biology, Utrecht University, Utrecht, The Netherlands.
authors.forename: R J
authors.initials: RJ
authors.lastname: de Boer
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000276:immunology; D000483:Alleles; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics* / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics* / Q000276:immunology; D018448:Models, Immunological; D011110:Polymorphism, Genetic / Q000235:genetics* / Q000276:immunology; D046988:Proteasome Endopeptidase Complex / Q000276:immunology; D014777:Virus Diseases / Q000276:immunology*
chemical_list: D018528:ATP-Binding Cassette Transporters; D000939:Epitopes; C477327:transporter associated with antigen processing (TAP); D046988:Proteasome Endopeptidase Complex