DESCRIPTION: The HIV pandemic is one of the greatest public health challenges in history. It is estimated that 33 million people are living with HIV and 2.7 million of those are newly infected In a number of developed countries, the risk of death associated with HIV-1 infection has sharply declined due to the use of highly active antiretroviral therapy (HAART). Unfortunately, the rate of new HIV infections remains undiminished, even with the ever increasing availability of prevention programs and HAART. For these reasons, a vaccine that could prevent or control the spread of HIV is urgently needed. A recent study showed that a skin-delivered therapeutic DNA vaccine co-formulated with a novel adjuvant stimulated mucosal T cell responses in SIV-infected macaques and led to durable viral suppression in a subset of animals after stopping ART. These results are in striking contrast to previous therapeutic vaccines employing intramuscular delivery of DNA that failed to induce an effect or at best, induced a 1-2 log reduction in viremia or transient control of viral rebound. We propose to make therapeutic DNA vaccination even more effective by 1) using a more potent combination of drugs (cART) to maximize the effects of the vaccine, 2) using a more potent adjuvant strategy that increases DNA vaccine induction of antibody and T cell responses and stimulates homing of these responses to gut associated lymphoid tissues, and 3) using a novel electroporation DNA delivery device that more efficiently delivers DNA into the skin (a more immunocompetent site than muscle for induction of systemic and mucosal responses). Our overarching hypothesis is that a vaccine-induced functional cure will be mediated by strong mucosal responses, and that increasing and focusing these responses to the gut in maximally suppressed infections via use of an optimized mucosal adjuvant and delivery into skin will maximally reduce or prevent residual viruses from emerging from the gut reservoir after stopping cART. To this end, we have assembled a panel of four DNA-based adjuvants that we hypothesize will induce robust anti-HIV mucosal and systemic immune responses when combined. Under this fast track SBIR, we will investigate adjuvant combinations with our HIV/SIV multi-antigen (MAG) DNA vaccine consisting of plasmids expressing env (gp160), a gag/pol fusion, and a nef/tat/vif fusion. We anticipate that an optimal combination of these adjuvants will elevate the performance of our MAG DNA vaccine to a level worthy of human trials.