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- Genome-wide association studies (GWAS) are used in a novel method of predicting residues in conserved epitopes with a high mutation cost to HIV fitness that are best targeted by a vaccine. Protein structure-based network analysis was used to quantify the topological importance of each residue to the tertiary and quaternary structure of HIV p24 protein as residue-residue interactions. A network score was generated for each residue (node) using data on non-covalent interactions (edges) - van der Waals interactions, hydrogen bonds, salt bridges, disulfide bonds, π-π interactions, π-cation interactions, metal-coordinated bonds and local hydrophobic packing. Residues of low-mutation tolerance were at important network positions and impaired viral replication fitness greatly. These residues were found in highly networked epitopes that were presented more often by protective HLA. Natural controllers of infection targeted more of these highly networked CTL epitopes, even in the absence of protective presenting HLA alleles.
- Comparison within 5,430 Clade B isolates showed an inverse relationship between network score and mutational frequency in 11 additional HIV proteins. Gag p24 was the most highly networked protein due to extensive capsid multimerization requirements, making it mutationally fragile and linking Gag-specific CTL breadth with lower VL.
- Experimental mutation of highly networked residues resulted in impairment of HIV infectivity at 2 days and viral replication at 7 days but mutation of residues with poor network scores was not impactful.
- Risk versus Protective HLA alleles were able to be delineated by averaging residue network scores involved in HLA binding, TCR recognition, and peptide processing of an epitope associated with that HLA allele. Protective vs. non-protective HLA of controllers, however, had no significant difference in their eptiopes' network scores.
- Neutral-HLA-restricted immunodominant epitopes of controller subjects contained much more highly networked residues than progressor subjects'. Controllers and progressors with similar CTL proliferation also had a significant difference in the sum of network scores of targeted epitopes.
- Protective epitope, B*57-KF11 contains highly networked residues that bridge the N- and C- terminal domains of Gag p24 and that contact HLA anchor and TCR sites. While A31 and F40 are HLA anchor residues, the rest of the residues - F32, S33, P34, E35, V36, I37, P38, M39 - contact TCR. It has a normalized network score of 8.78 and is presented by B*5701, B*5703 or B63.
- Supplementary Table S3 contains 260 Epitope Network Scores of HIV optimal CTL epitopes, pp. 25-27, http://science.sciencemag.org/content/suppl/2019/05/01/364.6439.480.DC1.
Gaurav D. Gaiha, Elizabeth J. Rossin, Jonathan Urbach, Christian Landeros, David R. Collins, Chioma Nwonu, Itai Muzhingi, Melis N. Anahtar, Olivia M. Waring, Alicja Piechocka-Trocha, Michael Waring, Daniel P. Worrall, Musie S. Ghebremichael, Ruchi M. Newman, Karen A. Power, Todd M. Allen, James Chodosh, and Bruce D. Walker. Structural Topology Defines Protective CD8+ T Cell Epitopes in the HIV Proteome. Science, 364(6439):480-484, 3 May 2019. PubMed ID: 31048489.
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