RIVM, Bilthoven, The Netherlands; Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Academic Biomedical Centre, Utrecht, The Netherlands; Faculty of Biology, Utrecht University, Utrecht, The Netherlands.
Epidemics. 2010 Sep;2(3):99-108. doi: 10.1016/j.epidem.2010.05.003. Epub 2010 Jun 9.
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.
经典的抗原呈递途径由两个单态（蛋白酶体和 TAP）和一个多态成分（MHC Ⅰ类）组成。病毒可以通过突变表位使其不再被途径正确处理来逃避 CTL 反应。虽然影响 MHC 结合的逃逸突变在下一个病毒宿主中不再受到选择压力（因为宿主在 MHC 等位基因上存在差异），但影响表位前体抗原加工的逃逸突变会阻止宿主群体中任何 MHC 等位基因使用这些表位前体。因此，病毒可能受到适应单态蛋白酶体和 TAP 的选择压力。我们设计了一个基于主体的宿主群体模型，其中类似于 HIV-1 的病毒适应个体宿主的抗原呈递途径，随着病毒在群体中的传播。我们研究了 MHC 的多态性以及蛋白酶体和 TAP 的单态性如何影响病毒可以达到的对宿主群体的适应水平。我们发现，由于 MHC Ⅰ类分子的多态性和高度特异性，不同宿主的 CTL 反应所针对的 CTL 表位并不共享许多表位前体。因此，表位前体中的逃逸突变经常从免疫选择压力中释放出来，并可以恢复到病毒野生型序列。因此，病毒适应蛋白酶体和 TAP 的选择压力相对较小，这解释了病毒对抗原呈递途径中单态步骤的低适应水平。
