Dataset Information

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

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-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.

SUBMITTER: Asbach B

PROVIDER: S-EPMC6062507 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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

Asbach Benedikt B Meier Johannes P JP Pfeifer Matthias M Köstler Josef J Wagner Ralf R

Scientific reports 20180726 1

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<sup>+</sup> T cell epitopes in HIV's Gag protein, respect ...[more]

PMID: 30050069

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Project description:Members of the Sarbecovirus subgenus of Coronaviridae have twice caused deadly threats to humans. There is increasing concern about the rapid mutation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has evolved into multiple generations of epidemic variants in 3 years. Broad neutralizing antibodies are of great importance for pandemic preparedness against SARS-CoV-2 variants and divergent zoonotic sarbecoviruses. Here, we analyzed the structural conservation of the receptor-binding domain (RBD) from representative sarbecoviruses and chose S2H97, a previously reported RBD antibody with ideal breadth and resistance to escape, as a template for computational design to enhance the neutralization activity and spectrum. A total of 35 designs were purified for evaluation. The neutralizing activity of a large proportion of these designs against multiple variants was increased from several to hundreds of times. Molecular dynamics simulation suggested that extra interface contacts and enhanced intermolecular interactions between the RBD and the designed antibodies are established. After light and heavy chain reconstitution, AI-1028, with five complementarity determining regions optimized, showed the best neutralizing activity across all tested sarbecoviruses, including SARS-CoV, multiple SARS-CoV-2 variants, and bat-derived viruses. AI-1028 recognized the same cryptic RBD epitope as the parental prototype antibody. In addition to computational design, chemically synthesized nanobody libraries are also a precious resource for rapid antibody development. By applying distinct RBDs as baits for reciprocal screening, we identified two novel nanobodies with broad activities. These findings provide potential pan-sarbecovirus neutralizing drugs and highlight new pathways to rapidly optimize therapeutic candidates when novel SARS-CoV-2 escape variants or new zoonotic coronaviruses emerge. IMPORTANCE The subgenus Sarbecovirus includes human SARS-CoV, SARS-CoV-2, and hundreds of genetically related bat viruses. The continuous evolution of SARS-CoV-2 has led to the striking evasion of neutralizing antibody (NAb) drugs and convalescent plasma. Antibodies with broad activity across sarbecoviruses would be helpful to combat current SARS-CoV-2 mutations and longer term animal virus spillovers. The study of pan-sarbecovirus NAbs described here is significant for the following reasons. First, we established a structure-based computational pipeline to design and optimize NAbs to obtain more potent and broader neutralizing activity across multiple sarbecoviruses. Second, we screened and identified nanobodies from a highly diversified synthetic library with a broad neutralizing spectrum using an elaborate screening strategy. These methodologies provide guidance for the rapid development of antibody therapeutics against emerging pathogens with highly variable characteristics.

Dataset Information

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

Publications

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

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