A Peptide Filtering Relation Quantifies MHC Class I Peptide Optimization
Figure 7
Simulation of cell surface presentation of HIV virus peptides by HLA–B2705.
The sequence of the HIV-1 polyprotein Gag-Pol was obtained from the UniProt online resource (accession P03367). All peptides between 8 and 10 amino acids in length were then derived from the sequence and assessed for their off-rates using the BIMAS prediction algorithm (http://www-bimas.cit.nih.gov/molbio/hla_bind [28]). The peptides were then simulated by assuming that they are all supplied into the ER via TAP at an equal rate, such that the total supply rate is equal to the total supply rate estimated for Fig. 4. As the algorithm predicted many peptides to have the same off-rate, peptides were clustered for ease of computation. (A) The number of peptides with a given peptide off-rate, as calculated by BIMAS. (B) Steady-state cell surface presentation of peptide-MHC complexes as a function of peptide off-rate. Peptide supply was assumed to be constant for each individual peptide. Therefore, the supply rate associated with a particular off-rate is simply scaled by the number of peptides with that off-rate, as quantified in A. The lowest off-rate (highest affinity) peptides for B2705 (KRWIILGLNK) and B4403 (AETQCETAY) are indicated. Simulations were performed for the presence and absence of tapasin, as indicated in the key. (C) Enhancement of cell surface presentation by tapasin was computed by dividing simulated tapasin-sufficient presentation by simulated tapasin-deficient presentation for each peptide. The results of the HIV simulations illustrate the extent to which tapasin can affect a downstream immune response. Theoretically, tapasin can enhance presentation by up to a factor , where
is the off-rate of the peptide from MHC (Fig. 5). However, the characteristics of the MHC allele, such as the allele-specific peptide on-rate, can significantly alter the effect of tapasin on the presentation of a given peptide. Our model allows differences in presentation levels to be quantified by taking into account peptide supply and peptide off-rate, together with the effects of tapasin and the binding properties of the MHC class I allele under consideration. In particular, our analysis of the HIV-1 Gag-Pol polyprotein provides a specific quantitative prediction for the cell surface presentation of the immunodominant KRWIILGLNK by HLA–B2705. By simulating the range of peptides derived from Gag-Pol, representing a range of off-rates, we observe that the enhancement by tapasin is independent of peptide supply, instead being wholly determined by the peptide off- and on-rates (Fig. 7 C).