Extensive study of HIV+ individuals in recent years has brought to light many examples of antibodies that can neutralize a broad range of HIV strains and protect against viral challenge in animal models of infection. The portion of viral surface most commonly targeted by such antibodies is now known to be the ?high-mannose patch?: among patients producing broadly-neutralizing antibodies, 38% target this one region of the virus. One of the most potent high mannose patch antibodies, PGT128, binds to a particular arrangement of high-mannose glycans and conserved peptide residues. Our goal is to develop vaccine immunogens which mimic this arrangement precisely and be used to elicit PGT128-like antibodies. Our approach will utilize unique directed evolution methods to develop glycopeptide immunogens in which PGT128 epitope elements are correctly reconstituted. It is also possible that additional immunogens will be required to correctly prime the immune response by stimulating germline precursors of PGT128. Therefore, we will develop glycopeptides targeting both mature and germline PGT128 antibodies. In collaboration with David Nemazee at Scripps, we will investigate the ability of these glycopeptides in combination, to activate a germline PGT128 response that can mature into a response with broadly-neutralizing PGT128-like specificity.
It is now recognized that some HIV-infected individuals are capable of producing antibodies that neutralize many different strains of HIV, despite the virus' ability to mutate. These antibodies bind to the most vulnerable surfaces on the virus, and thus teach us how to design better vaccines. The goal of this project is to create and test vaccines which are designed for their ability to bind to this antibody and mimic the virus.
| Horiya, Satoru; Bailey, Jennifer K; Krauss, Isaac J (2017) Directed Evolution of Glycopeptides Using mRNA Display. Methods Enzymol 597:83-141 |
