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HLA Alleles Associated with Slow Progression to AIDS Truly Prefer to Present HIV-1 p24 ´ 1,2 3 1 1,3,4 Jose A. M. Borghans , Anne Mølgaard , Rob J. de Boer , Can Kes¸mir * 1Theoretical Biology/Bioinformatics, Utrecht University, Utrecht, The Netherlands, 2 Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands, 3 Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark, 4 Academic Biomedical Centre, Utrecht University, Utrecht, The Netherlands Background. The 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 Findings. 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. 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. Conclusions. Our results