Host genotype and time dependent antigen presentation of viral peptides: predictions from theory

Abstract

The rate of progression of HIV infected individuals to AIDS is known to vary with the genotype of the host, and is linked to their allele of human leukocyte antigen (HLA) proteins, which present protein degradation products at the cell surface to circulating T-cells. HLA alleles are associated with Gag-specific T-cell responses that are protective against progression of the disease. While Pol is the most conserved HIV sequence, its association with immune control is not as strong. To gain a more thorough quantitative understanding of the factors that contribute to immunodominance, we have constructed a model of the recognition of HIV infection by the MHC class I pathway. Our model predicts surface presentation of HIV peptides over time, demonstrates the importance of viral protein kinetics, and provides evidence of the importance of Gag peptides in the long-term control of HIV infection. Furthermore, short-term dynamics are also predicted, with simulation of virion-derived peptides suggesting that efficient processing of Gag can lead to a 50% probability of presentation within 3 hours post-infection, as observed experimentally. In conjunction with epitope prediction algorithms, this modelling approach could be used to refine experimental targets for potential T-cell vaccines, both for HIV and other viruses.

A Mechanistic Model for Predicting Cell Surface Presentation of Competing Peptides by MHC Class I Molecules

“…Prediction of an entire cell surface peptide repertoire would, therefore, require high-throughput measurements of protein expression and turnover by quantitative proteomics (SILAC) ( 55 ), or measurements of transcription levels or protein translation rates, combined with proteasomal cleavage ( 56 ) and TAP binding ( 57 ) predictions. The dynamical modeling approach that we advocate ( 26 , 58 ) has the advantage of encoding mechanistic hypotheses, which should enable us to also predict how peptide presentation changes under a range of genetic or physiological perturbations to the antigen presentation machinery.…”

When we can trust computers (and when we can't)

“…Despite the caveat that computers are made and used by people, there is also considerable interest in their use to design and run experiments, for instance using Bayesian optimization methods, such as in the field of cognitive neuroscience [ 81 ] and to model infectious diseases and immunology quantitatively [ 82 ].…”

“…82 Despite the caveat that computers are made and used by people, there is also considerable interest in their use to design and run experiments, for instance using Bayesian optimization methods, such as in the field of cognitive neuroscience 83 and to model infectious diseases and immunology quantitatively. 84 When it comes to the limitations of digital computing, research is under way by Boghosian and PVC to find alternative approaches that might render such problems computable on digital computers. Among possible solutions, one that seems guaranteed to succeed is analogue computing, an older idea, able to handle the numerical continuum of reality in a way that digital computers can only approximate.…”

The influence of HLA/HIV genetics on the occurrence of elite controllers and a need for therapeutics geotargeting view

“…Eccleston et al. 44 simulated the HIV-1 clade C peptide presentation on TCL surface with bioinformatics tools, which predicts the peptidome of an amino acid sequence, the probability of proteasomal cleavage, TAP affinity, and the affinity (IC50) between the peptide and chosen MHC-I. These pieces of information were combined in a score.…”

“…Among nine HIV-1 proteins, Gag peptides predominate at the cell surface, with a Gag:Pol ratio of 18:1, a Gag:Vpr ratio of 23:1, and a Gag:Env ratio of 64:1, and the Env protein was the third most abundant in the cytoplasm, but its epitope is just the sixth most abundant on the cell surface. 44 …”