PROJECT SUMMARY/ABSTRACT Induction of broadly neutralizing antibodies (bnAbs) against HIV-1 is the utmost critical goal towards the development of a protective AIDS vaccine. In this proposal, we will evaluate a novel “Antigen-Enhanced, Anti-Idiotypic Antibody (AEAIA)” vaccine strategy to elicit PGT128-like bnAbs against HIV-1. PGT128, a bnAb isolated from a HIV-1-infected patient, has been shown to neutralize ~72% of all HIV-1 isolates tested. Furthermore, PGT128 is highly potent with median IC50 of 0.02 µg/ml. Establishment of a vaccine strategy that can induce PGT128-like bnAbs would be a major milestone towards AIDS vaccine development. Thus, our proposal is highly significant and, if successful, this project will have great impact in the AIDS vaccine field and the immunogens we generate will have a significant commercial value. This proposal is based on a scientific premise that a priming immunogen (primogen) plays a critical role in generating a B-cell repertoire that will determine antibody responses during subsequent exposures to antigenically related boosting immunogens. As such, developing a primogen that can induce antibodies directed predominantly against the PGT128 neutralizing epitope is of paramount importance. The major innovation and the focus of this proposal is AEAIA vaccine strategy, in which immune- complexes are used as immunogens. Although the process is conceptually similar to generating PGT128-like anti-anti- idiotypic antibodies, our strategy is technically distinct and superior in that we are using an antigen-antibody immune complex as an immunogen. The primary objective of this study is to generate mV3-antibody complexes that could be used as a primogen to induce PGT128-like bnAbs, or at least induce a large repertoire of antibodies that target the PGT128 neutralizing epitope, which could be further refined by sequential boosting with progressively more native envelope antigens. Successful completion of this study would overcome a critical roadblock towards development of a protective AIDS vaccine.