PROJECT SUMMARY/ABSTRACT Broadly neutralizing antibodies are likely to be an important component of an HIV-1 vaccine. The HIV-1 Envelope (Env) glycoprotein is the sole target of neutralizing antibodies and has been a focus of immunogen designs. Yet diverse recombinant (rec) Envs do not display detectable binding to the inferred germline (iGL) of certain bNAbs, such as the VRC01-class bNAbs, which are the focus of our HIVRAD project. Rec Envs capable of binding iGL VRC01 bNAbs have been designed and induced the production of iGL VRC01 bNAbs when used as immunogens. However these novel immunogens are not sufficient to induce the maturation of iGL VRC01- class bNAbs to their broad neutralization forms. In this HIVRAD, we propose to use novel reagents as immunogens to guide the development of VRC01-class bNAbs. The Reagents and Structural Core will provide high quality reagents to Projects 1-3 of this HIVRAD as well as structural information on all antibodies described and obtained in this HIVRAD (vaccine-elicited or from naïve humans or animals) in complex with their epitopes. This information will help us to better understand the B cell response elicited by our novel immunogens and will assist us in improving our “prime-boost” schemes.