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Title page for ETD etd-09082018-120634


Type of Document Dissertation
Author Sevy, Alexander Mario
Author's Email Address alex.sevy@gmail.com
URN etd-09082018-120634
Title Engineering cross-reactivity in the antibody response to HIV and influenza
Degree PhD
Department Chemical and Physical Biology
Advisory Committee
Advisor Name Title
Spyros Kalams Committee Chair
James Crowe Committee Member
James Thomas Committee Member
Jens Meiler Committee Member
Melanie Ohi Committee Member
Terry Lybrand Committee Member
Keywords
  • structural immunology
  • reverse vaccinology
  • antibody design
  • protein design
Date of Defense 2018-08-30
Availability restricted
Abstract
Antibodies are a key component of the human immune response to infectious disease. The best anti-viral antibody response is one that is potent and broad, covering a large number of the many diverse viral variants. Unfortunately, natural human antibodies are rarely perfect in that they don’t cover the entire spectrum of possible viral variants. In this thesis, I describe my work using computational design with the ROSETTA software to re-engineer human antibodies to improve their coverage of large viral panels, also known as their breadth. I developed two new methods for increasing the scale of computational design against many viral proteins, a technique known as multistate design, and applied one of these methods to an anti-influenza system to define the molecular limits of breadth and affinity. In addition, I use computational modeling to identify and optimize antibodies that cross-react between different viral proteins. Finally, I use computational modeling to engineer peptides capable of recapitulating the activity of a broadly neutralizing antibody with increased breadth.

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