Abstract
BackgroundThe mechanism behind the association between human leukocyte antigen (HLA) molecules and the rate of HIV-1 disease progression is still poorly understood. Recent data suggest that “protective” HLA molecules, i.e. those associated with a low HIV-1 viral load and relatively slow disease progression, tend to present epitopes from the Gag capsid protein. Although this suggests that preferential targeting of Gag delays disease progression, the apparent preference for Gag could also be a side-effect of the relatively high immunogenicity of the protein.Methods and FindingsTo separate cause and effect, we predicted HIV-1 epitopes from the whole genome of HIV-1, and found that protective HLA alleles have a true preference for the p24 Gag protein, while non-protective HLA alleles preferentially target HIV-1 Nef. In line with this, we found a significant negative correlation between the predicted affinity of the best-binding p24 epitopes and the relative hazard of HIV-1 disease progression for a large number of HLA molecules. When the epitopes targeted by protective HLA alleles were mapped to the known p24 structure, we found that mutations in these epitopes are likely to disturb the p24 dimer structure, which is expected to severely reduce the fitness of the virus.ConclusionsOur results suggest that the intrinsic preference of different HLA molecules to present p24 peptides explains why some HLA molecules are more protective than others.
Highlights
There is increasing evidence that human leukocyte antigen (HLA) molecules influence the rate of disease progression after HIV-1 infection
We studied the HLA-binding affinities of HIV-1 peptides for HLA-B5701, B5801, and B2705, three HLA alleles with a clearly low relative hazard (RH) of HIV disease progression [1] (Figure 1, Low RH, open and shaded symbols), and for HLA-B3503 and B5301, which are both associated with relatively rapid HIV-1 disease progression [1] (Figure 1, High RH, solid symbols)
We plotted the ranks of the three best-binding peptides from each HIV-1 protein among all other HIV epitopes, because Kiepiela et al [23] reported that the presence of Cytotoxic T lymphocyte (CTL) responses against at least two Gag-epitopes is associated with a low HIV-1 viral load
Summary
There is increasing evidence that human leukocyte antigen (HLA) molecules influence the rate of disease progression after HIV-1 infection (reviewed in [1]). Recent data suggest that ‘‘protective’’ HLA molecules, i.e. those associated with a low HIV-1 viral load and relatively slow disease progression, tend to present epitopes from the Gag capsid protein. This suggests that preferential targeting of Gag delays disease progression, the apparent preference for Gag could be a side-effect of the relatively high immunogenicity of the protein. To separate cause and effect, we predicted HIV-1 epitopes from the whole genome of HIV-1, and found that protective HLA alleles have a true preference for the p24 Gag protein, while non-protective HLA alleles preferentially target HIV-1 Nef. In line with this, we found a significant negative correlation between the predicted affinity of the best-binding p24 epitopes and the relative hazard of HIV-1 disease progression for a large number of HLA molecules. Our results suggest that the intrinsic preference of different HLA molecules to present p24 peptides explains why some HLA molecules are more protective than others
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