The overall mission of this CHAVI-ID application is to define immunogens and immunization regimens that induce sustained HIV cross-protective B cell and CD4+ T cell responses in preclinical models and, thereby, guide product development strategies for a preventive human AIDS vaccine. Focus #1 will concentrate on B cell and antibody research to facilitate the development of immunogens and immunization protocols that elicit protective broadly neutralizing antibody responses. Our overall strategy in this focus can be briefly summarized in the following goals: 1) To fully define a comprehensive map of the broadly neutralizing (bn) epitopes of the HIV Env spike. Breakthroughs in generating broadly neutralizing human monoclonal antibodies (bnMAbs) in the last two years are bringing this goal within reach; 2) To determine which of the HIV bnMAbs provide the most effective protection against viral challenge in the non-human primate (NHP) model. At the same time, we shall closely monitor developments in the field, including suggestions that some non-neutralizing antibodies may have protective qualifies that might be exploited in vaccine discovery; 3) To determine which HIV broadly neutralizing Abs (bnAbs) are most readily elicited through natural infection and how and when they are elicited using several large cohorts to which we have unique access; 4) To determine which immunogens and immunization strategies best stimulate HIV bnAb generation in the knock-in mouse and NHP models, drawing upon data collected on bnAbs in goals 1-3 and emerging from Focus #2. As we gather together information on optimal immunogens and immunization strategies, we will move forward with small-scale human trials with the advice and close involvement of our Vaccine Discovery Scientific Research Support Component.