Abstract
The large diversity in MHC class I molecules in a population lowers the chance that a virus infects a host to which it is pre-adapted to escape the MHC binding of CTL epitopes. However, viruses can also lose CTL epitopes by escaping the monomorphic antigen processing components of the pathway (proteasome and TAP) that create the epitope precursors. If viruses were to accumulate escape mutations affecting these monomorphic components, they would become pre-adapted to all hosts regardless of the MHC polymorphism. To assess whether viruses exploit this apparent vulnerability, we study the evolution of HIV-1 with bioinformatic tools that allow us to predict CTL epitopes, and quantify the frequency and accumulation of antigen processing escapes. We found that within hosts, proteasome and TAP escape mutations occur frequently. However, on the population level these escapes do not accumulate: the total number of predicted epitopes and epitope precursors in HIV-1 clade B has remained relatively constant over the last 30 years. We argue that this lack of adaptation can be explained by the combined effect of the MHC polymorphism and the high specificity of individual MHC molecules. Because of these two properties, only a subset of the epitope precursors in a host are potential epitopes, and that subset differs between hosts. We estimate that upon transmission of a virus to a new host 39%–66% of the mutations that caused epitope precursor escapes are released from immune selection pressure.
Highlights
Antigen presentation allows CD8+ T cells to monitor the protein content of a cell and detect the presence of intracellular viruses [1]
Adaptation to the human population To determine whether HIV has exploited the lack of polymorphism of the proteasome and transporter associated with antigen processing (TAP), we predicted the number of epitope precursors in a human immunodeficiency virus 1 (HIV-1) clade B sequence population data set with samples from 1980 to 2005
In all three cases there was no sign of any large-scale adaptation of HIV-1 clade B to its human host over the last 30 years: the number of epitope precursors, major histocompatibility complex (MHC)-binding peptides and Cytotoxic T lymphocytes (CTL) epitopes per HIV-1 sequence remained constant over time
Summary
Antigen presentation allows CD8+ T cells to monitor the protein content of a cell and detect the presence of intracellular viruses [1]. The peptide fragments that are processed by the proteasome and transported by TAP are commonly called ‘epitope precursors’ Of these three steps in the antigen presentation pathway it is only the MHC that is highly polymorphic, which is thought to have evolved because of the rare allele advantage [6,7,8]: hosts that carry rare MHC alleles are less likely to be infected by viruses that are adapted to escape the host’s MHC alleles than hosts with common MHC alleles, because it is less likely that these viruses come from a host with the same rare MHC alleles. If viruses adapt to escape the epitope precursors [12,13,14,15], which are created by the monomorphic proteasome and TAP, the protective effect of the MHC polymorphism and the fitness advantage of hosts with rare MHC alleles would be lost
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