Broad coverage of the pathogen population is particularly important when designing CD8+ T-cell epitope vaccines against viral pathogens. Traditional approaches are based on combinations of highly conserved T-cell epitopes. Peptide block entropy analysis is a novel approach for assembling sets of broadly covering antigens. Since T-cell epitopes are recognized as peptides rather than individual residues, this method is based on calculating the information content of blocks of peptides from a multiple sequence alignment of homologous proteins rather than using the information content of individual residues. The block entropy analysis provides broad coverage of variant antigens. We applied the block entropy analysis method to the proteomes of the four serotypes of dengue virus (DENV) and found 1,551 blocks of 9-mer peptides, which cover 99% of available sequences with five or fewer unique peptides. In contrast, the benchmark study by Khan et al. (2008) resulted in 165 conserved 9-mer peptides. Many of the conserved blocks are located consecutively in the proteins. Connecting these blocks resulted in 78 conserved regions. Of the 1551 blocks of 9-mer peptides 110 comprised predicted HLA binder sets. In total, 457 subunit peptides that encompass the diversity of all sequenced DENV strains of which 333 are T-cell epitope candidates.
2 11 newly generated MCC lines through genomic and proteomic analysis. We then interrogated MCC lines through genome-scale gain-and loss-of-function screens for the restoration of HLA-I. These screens identified MYCL and the non-canonical Polycomb repressive complex 1.1 (PRC1.1) as regulators of HLA-I. We further demonstrate that pharmacologic inhibition of the PRC1.1 component USP7 can restore HLA-I expression.
The majority of antibody binding sites (B-cell epitopes) on antigens are discontinuous. The binding between antigen and antibody is specific, but in some cases, the antibody elicited by one antigen will show cross-reactivity against other antigens. We have developed a bioinformatics-based approach for the analysis of sequence variability of neutralizing antibody binding sites and the assessment of coverage by individual neutralizing antibodies. The antigenic analysis of functional sites on the envelope (E) protein from dengue virus has been used as a case study. The description of B-cell epitopes, measurement of epitope similarity among different strains, and estimation of antibody neutralizing coverage provide insights in antibody cross-reactivity. We have defined a generalized method for the analysis of cross-reactivity of neutralizing antibodies that is also applicable to the analysis of other pathogens. This method adds to the toolset available for the characterization and the design of broadly neutralizing vaccines.
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