Date of Award
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Bachelor of Arts
Chemistry & Biochemistry
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.
Finkelstein, Maxwell T. , '22, "Characterization of the DH475 cooperating antibody and its interaction with the HIV-1 spike" (2022). Senior Theses, Projects, and Awards. 256.