The Holy Grail of HIV vaccine development is an immunogen that elicits antibodies that broadly neutralize field strains of the virus. While tremendous insights have been gained into the structure and function of the HIV envelope glycoprotein, precious little progress has been made in designing such immunogens. In fact, it remains formally possible that with current technologies, engagement of the adaptive immune system will not lead to an effective HIV vaccine. Considering this possibility, we have taken a markedly different approach to the generation of serum neutralizing activity against HIV, dubbed “reverse immunization.” In this model, we select the antibody or antibody-like molecule of interest (ie, one that broadly neutralizes), then synthetically derive the representative gene and place it into the context of an adeno-associated virus (AAV) gene transfer vector. When injected intramuscularly into a vaccinee, the AAV vector genome directs in vivo production of the gene product that leads to serum neutralizing activity against HIV. Recently, we have refined this approach for the SIV model system, and can now provide in a single dose, sterilizing immunity to vaccinated monkeys against a virulent SIV challenge virus. Thus, reverse immunization holds significant promise as a “designer” approach to an effective HIV vaccine.