Based on our understanding of envelope-based mechanisms of humoral evasion, we have attempted to design envelope-based immunogens with these mechanisms disabled. Such modied immunogens with weakened defenses may elicit more broadly neutralizing antibodies. We have also devised scaffolding technologies, as a means of presenting structural mimics of the epitopes of broadly neutralizing antibodies to assist in their re-elicitation. Scaffolds can be non-homologous proteins, identified through searches of the entire protein data bank. Alternatively, scaffolds can be homologous proteins, which are structurally similar, but antigenically distinct from the HIV-1 envelope glycoproteins. An alternative to scaffolding involves """"""""resurfacing"""""""", where the surface of a molecule, not involved in eliciting a desired response, is altered between """"""""prime"""""""" and """"""""boost"""""""" phases of immunization. Finally we have investigated both molecular motion and expression-system-dependent modulation of HIV-1 envelope antigenicity and immunogenicity.
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