Novel approaches for the generation of more effective vaccines for HIV-1 are of significant importance. In this report we analyse the immunogenicity and efficacy of a DNA vaccination approach in a chimpanzee model system. Three chimpanzees were vaccinated with DNA constructs which express the env, rev, gag and pol proteins. These animals developed specific cellular responses to these proteins, although the nature of the responses varied among the animals. We demonstrated that DNA vaccination led to a CD8 mediated killing of targets expressing the homologous clade B envelope as well as targets expressing heterologous clade E envelope. In addition seronegative individuals have been inoculated with a DNA construct which expresses the env, rev proteins. These studies serve as an important benchmark for the use of DNA vaccine technology for the production of protective immune responses.