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On Epitope-Paratope Interactions of Emerging to Endemic Viruses

The spectrum of viruses ranges from emerging viruses such as Nipah virus (NiV), which sporadically seeds local outbreaks with high mortality, to continually drifting endemic viruses such as influenza A (flu). Meanwhile, SARS-CoV-2 is currently transitioning from an emergent to an endemic virus with unknown evolutionary potential. Though highly differentiated, these three viruses present a common challenge to scientists, clinicians, and public health officials in the need to continually prepare for and rapidly respond to new outbreaks, novel variants, and persistent antigenic drift.

Viruses present numerous epitope surfaces that are recognized by the human host immune system upon infection. Infected hosts develop antibodies that bind virus epitopes via the antibody’s paratope in an epitope-paratope interaction (EPI). Studying EPIs enables us to better understand viral pathogenesis, model viral evolution, and develop vaccines and therapeutic antibodies.

In this thesis, we present a series of EPI analyses of NiV, flu, and SARS-CoV-2 that enrich our understanding of these viruses and serve as the basis for therapeutic antibody design, optimization, and repurposing. In particular, our work focuses on epitope features driving epitope complexity, such as N-glycans and higher-order protein structures that produce allosteric and epistatic relationships. We develop methods and tools to analyze these complex epitope features—which critically influence antibody function and viral escape—with applications across the viral spectrum. Key products of this work include the identification of putative repurposing targets for an anti-HIV antibody and a rapid assessment of Omicron BA.1 variant escape from authorized therapeutic antibodies.

Thesis Supervisor:
Ram Sasisekharan, PhD
Alfred H. Caspary Professor of Biological Engineering, MIT

Thesis Committee Chair:
Peter Dedon, MD, PhD
Underwood-Prescott Professor of Biological Engineering, MIT

Thesis Committee Member:
Shiv Pillai, MD, PhD
Professor of Medicine and Health Sciences & Technology, HMS

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Nathaniel Loren Miller is inviting you to a scheduled Zoom meeting.

Topic: Nathaniel Miller PhD Thesis Defense
Time: Monday, May 23, 2022 3:00 PM Eastern Time (US and Canada)

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