Asbach, Benedikt and Meier, Johannes P. and Pfeifer, Matthias and Koestler, Josef and Wagner, Ralf (2018) Computational Design of Epitope-Enriched HIV-1 Gag Antigens with Preserved Structure and Function for Induction of Broad CD8(+) T Cell Responses. SCIENTIFIC REPORTS, 8: 11264. ISSN 2045-2322,
Full text not available from this repository. (Request a copy)Abstract
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-cellepitope-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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | VIRUS-LIKE PARTICLES; IMMUNODEFICIENCY-VIRUS; IMMUNE-RESPONSES; RHESUS-MONKEYS; VACCINE DESIGN; DNA PRIME; CLASS-I; INFECTION; BREADTH; DIVERSITY; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Medizinische Mikrobiologie und Hygiene |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 06 Mar 2020 12:46 |
| Last Modified: | 06 Mar 2020 12:46 |
| URI: | https://pred.uni-regensburg.de/id/eprint/14208 |
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