Computational Design of Epitope-Enriched HIV-1 Gag Antigens with Preserved Structure and Function for Induction of Broad CD8+ T Cell Responses

The partially protective phenotype observed in HIV-infected long-term-non-progressors is often associated with certain HLA alleles, thus indicating that cytotoxic T lymphocyte (CTL) responses play a crucial role in combating virus replication. However, both the vast variability of HIV and the HLA di...

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Bibliographic Details
Published in:Scientific reports 2018-07, Vol.8 (1), p.11264-15, Article 11264
Main Authors: Asbach, Benedikt, Meier, Johannes P., Pfeifer, Matthias, Köstler, Josef, Wagner, Ralf
Format: Article
Language:English
Subjects:
631/250/2152/1566
631/250/255/1901
631/250/590
631/326/596/1787
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Antigen presentation
Antigens
CD8 antigen
Computer applications
Conserved sequence
Cytotoxicity
Design
Epitopes
Gag protein
Histocompatibility antigen HLA
HIV
Human immunodeficiency virus
Humanities and Social Sciences
Lymphocytes T
multidisciplinary
Phenotypes
Preservation
Science
Science (multidisciplinary)
Structure-function relationships
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Summary:The partially protective phenotype observed in HIV-infected long-term-non-progressors is often associated with certain HLA alleles, thus indicating that cytotoxic T lymphocyte (CTL) responses play a crucial role in combating virus replication. However, both the vast variability of HIV and the HLA diversity impose a challenge on elicitation of broad and effective CTL responses. Therefore, we conceived an algorithm for the enrichment of CD8 + T cell epitopes in HIV’s Gag protein, respecting functional preservation to enable cross-presentation. Experimentally identified epitopes were compared to a Gag reference sequence. Amino-acid-substitutions (AAS) were assessed for their impact on Gag’s budding-function using a trained classifier that considers structural models and sequence conservation. Experimental assessment of Gag-variants harboring selected AAS demonstrated an apparent classifier-precision of 100%. Compatible epitopes were assigned an immunological score that incorporates features such as conservation or HLA-association in a user-defined weighted manner. Using a genetic algorithm, the epitopes were incorporated in an iterative manner into novel T-cell-epitope-enriched Gag sequences (TeeGag). Computational evaluation showed that these antigen candidates harbor a higher fraction of epitopes with higher score as compared to natural Gag isolates and other artificial antigen designs. Thus, these designer sequences qualify as next-generation antigen candidates for induction of broader CTL responses.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-018-29435-1