In this study we propose to continue to develop an anti-idiotype (anti-id) -based strategy for eliciting and/or boosting broadly neutralizing antibodies against HIV. The principle of this approach is based on clonotypic stimulation which utilizes anti-id as surrogate for antigen in an attempt to stimulate specific elements of the B cell repertoire in humans. In phase I of this study, one anti-id Mab (3C9) was identified which induced broadly neutralizing anti-gp12O antibodies in immunonaive monkeys. Our studies will be extended to identify the utility of 3C9 to boosting titers of broadly neutralizing anti-gp12O antibodies. This aim will be achieved by determining the immunogenicity of 3C9 when tested in HIV-infected individuals and gp120 immune monkeys. In parallel, our efforts will continue to develop new anti-id Mabs which may be superior to 3C9 with respect to their potential as both prophylactic and therapeutic vaccines. We will generate anti-id Mabs which interact with the most prevalent, broadly neutralizing antibodies in the sera of HIV-infected individuals and vaccinated volunteers. These anti-id Mabs will be tested to determine whether they are capable of inducing and boosting the anti-gp12O titer in naive and gp12O primed cynomolgus monkeys. By comparing these results with that of 3C9, we will define new anti-id Mabs for clinical studies. In practice, the anti-id Mabs could be used as a therapy for HIV+ individuals and a prophylactic vaccine when combined with gp12O immunizations.