Project Summary/Abstract 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 glycoimmunogens 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.