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.
Highlights
The human immunodeficiency virus (HIV) is a fast mutating lentivirus that infects and eventually depletes T helper (Th) cells which are integral to adaptive immunity in vertebrates
Peptides are transported into the endoplasmic reticulum (ER) via transporter associated with antigen processing (TAP) molecules, where they can bind to Major Histocompatibility Complex (MHCI)
To determine the extent to which the association between Gag epitopes and HIV control may be predicted from static models of peptide processing and MHCI binding, we used the MHCI processing tools from Immune Epitope Data Base (IEDB)
Summary
The human immunodeficiency virus (HIV) is a fast mutating lentivirus that infects and eventually depletes T helper (Th) cells which are integral to adaptive immunity in vertebrates. Several HLA alleles such as B*58, B*57, B*27 and B*44 have been found to be over-represented among LTNPs and ECs, and they are associated with Gag-specific CTL responses[7,8,9,10,11] Many of these Gag-specific peptides originate from highly conserved regions of the Gag protein sequence[12] and so escape mutations will likely lead to diminished viral fitness. Pol protein sequence is known to be the most conserved in the HIV genome[7], but association between Pol-specific T-cell responses and immune control of HIV is not as convincing Another factor that might influence why Gag is so dominant in HIV control is peptide abundance. Intracellular protein abundance is an important factor when trying to predict CTL epitopes
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