Computational Design of Immunogens to ‘Re-elicit’ Neutralizing Antibodies

Seminar

Title: Computational Design of Immunogens to ‘Re-elicit’ Neutralizing Antibodies

Speaker: Bill Schief

Affiliation: Department of Biochemistry, University of Washington, Seattle, WA, USA

Hosts: Cláudio Soares and António Baptista

Abstract:

Given the structure of a neutralizing antibody in complex with its epitope, how can one design immunogens to ‘re-elicit’ antibodies with similar specificity? Answers to this question form the basis for much work in structure-based immunogen design, and may lead to vaccines for viruses such as HIV or Influenza. Our work focuses in part on developing computational methods to answer this question. We will discuss methods and results on design of non-HIV protein scaffolds presenting conserved HIV epitopes of known structure. “Epitope-scaffolds” are designed with atomic detail to stabilize the antibody-bound conformation of the epitope on the surface of the scaffold. By displaying conserved HIV epitopes in non-HIV scaffolds, we hope to bypass mechanisms of humoral evasion and induce the immune system to make “broadly-neutralizing” antibodies that neutralize diverse HIV strains. For two different conserved HIV epitopes, biophysical and crystallographic analysis of multiple epitope-scaffolds reveals high affinity binding to the target antibody and, in the best cases, near perfect structural mimicry of the antibody-bound epitope conformation. Immune responses to the epitope-scaffolds will also be discussed.