Date of Award

Spring 2022

Document Type

Restricted Thesis

Terms of Use

© 2022 Maxwell T. Finkelstein. All rights reserved. Access to this work is restricted to users within the Swarthmore College network and may only be used for non-commercial, educational, and research purposes. Sharing with users outside of the Swarthmore College network is expressly prohibited. For all other uses, including reproduction and distribution, please contact the copyright holder.

Degree Name

Bachelor of Arts

Department

Chemistry & Biochemistry

First Advisor

Daniela Fera

Abstract

HIV-1 evolves very quickly, so approaches to design an effective vaccine that elicits protective antibodies have thus far been unsuccessful. Current HIV vaccine design efforts seek to elicit broadly neutralizing antibodies, unique antibodies that target many viral variants, by first eliciting their precursors through prime-boost regimens. This requires an understanding of the co-evolution between viruses and antibodies. Towards this goal, we are analyzing a cooperating antibody, called DH475, which exerted pressure on HIV to evolve in such a way that it became sensitive to the DH270 broadly neutralizing antibody lineage. This study aims to elucidate how DH475 binds to the HIV viral spike, Env, and identify how DH475 facilitated the development of DH270 broadly neutralizing antibodies. We obtained a 2.90Å crystal structure of DH475 in complex with the Man9 glycan, and used site-directed mutagenesis coupled with biolayer interferometry (BLI) and protein-protein docking to characterize how DH475 interacts with Env. These investigations revealed a V3 glycan-dependent epitope accessible on an open gp120 monomer. While further confirmation of DH475’s binding mode is required, our findings suggest that DH475 may have selected for mutation of the N413 V4 glycan during HIV-1 infection of donor CH848. This may inform prime-boost regimens in which an initial immunogen bears the N413 glycan, while the boosting immunogen lacks this glycan and may facilitate the development of DH270-like broadly neutralizing antibodies.

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