The goal of this study is to enhance the immunogenicity and elicit high levels of neutralizing antibody to the HIV-1 envelope protein by using a component of the innate immune system, C3d, as a molecular adjuvant fused to soluble, stable trimers of envelope (Env) glycoprotein, sgp 140. Mice vaccinated with three copies of murine C3d (mC3d) fused to monomers of soluble gpl20 Env elicit higher titers and enhanced avidity maturation of antibodies to sgpl20mC3d, but only modest levels of neutralizing antibodies were detected. A trimeric form of Env that more closely resembles its native conformation elicits high levels of neutralizing antibodies, which were capable of neutralizing both X4 and R5 HIV- 1strains in mice vaccinated with sgpl40. The hypothesis is that soluble, stable trimers of gpl40 fused toC3d will enhance immunogenicity and elicit high levels of neutralizing antibody titers to HIV-1 Env.Codon optimized DNA plasmids expressing sgpl40 fused to 1,2, or 3 copies of murine C3d will be constructed in Aim 1 and tested for efficient secretion, presentation of Env, and stability. These vaccine plasmids will then be inoculated into mice in Specific Aim 2 in a dose response to identify the best immunogen capable of eliciting high titer neutralizing antibodies at the lowest dose of DNA. After successful completion of these mouse studies and identification of the most immunogenic sgpl40mC3dfusion protein, DNA vaccines expressing sgp 140 fused to two primate homologues of C3d will be tested for enhanced immunogenicity in specific Aim 3 to show that primate C3d elicits the same response.