"Innovative vectors and strategies are hardly needed to generate safe and efficacious HIV vaccines. Many types of recombinant viruses and DNA vectors have been used to induce protective immunity in the macaque model of HIV vaccine. However, the extent of protection achieved by these vaccines remains disappointing compared to Live-attenuated vaccines. We focused in development of lentiviral-based vectors as DNA vaccines and have shown that our first generation vector was efficient alone to induce protection of monkeys from AIDS following challenge with highly pathogenic homologous virus. We recently characterized the immune responses associated with this protection in immunized macaques. In this project we developed novel lentiviral vectors (lentivector) that have never been tested before. These lentivectors are non-integrating (NONI-LV) into the host genome and are driven by LTRs that have constitutive promoters. These innovative vectors synergize the properties, without the inconvenient, of both DNA and Live-attenuated vaccines. We hypothesize that these vectors will induce responses strong enough to induce protection against heterologous challenge viruses. Our long term goal is to develop safe and efficacious prophylactic vaccines against HIV in humans. The goal of the present project is to evaluate the immunogenicity and the safety of our novel NONI-LV vectors and the protection against pathogenic viruses in the non-human primate model of HIV. The work plan includes 4 major specific aims. In aim 1, we will focus on the safety of this type of vector by demonstrating their inability to integrate into the host genome. In aim 2 we will explore the immunogenicity of this vaccine vector in humanized SCID/NOD mice compared to our first generation vector. In aim 3 we will explore the immune responses induced in monkeys. In aim 4 we will explore the efficacy of induced immune responses to protect immunized monkeys against heterologous pathogenic viruses."