HIV-1 remains a major public health issue worldwide in spite of efficacious antiviral therapies, but with no cure or preventive vaccine. The latter has been very challenging, as virus infection is associated with numerous escape mechanisms from host specific immunity and the correlates of protection remain incompletely understood. We have developed an innovative vaccine strategy, inspired by the efficacy of live-attenuated virus, but with the safety of a DNA vaccine, to confer both cellular and humoral responses. The CAL-SHIV-IN− lentiDNA vaccine comprises the backbone of the pathogenic SHIVKU2 genome, able to mimic the early phase of viral infection, but with a deleted integrase gene to ensure safety precluding integration within the host genome. This vaccine prototype, constitutively expressing viral antigen under the CAEV LTR promoter, elicited a variety of vaccine-specific, persistent CD4 and CD8 T cells against SIV-Gag and Nef up to 80 weeks post-immunization in cynomolgus macaques. Furthermore, these specific responses led to antiviral control of the pathogenic SIVmac251. To further improve the efficacy of this vaccine, we incorporated the IL-7 or IL-15 genes into the CAL-SHIV-IN− plasmid DNA in efforts to increase the pool of vaccine-specific memory T cells. In this study, we examined the immunogenicity of the two co-injected lentiDNA vaccines CAL-SHIV-IN− IRES IL-7 and CAL-SHIV-IN− IRES IL-15 in BALB/cJ mice and rhesus macaques and compared the immune responses with those generated by the parental vaccine CAL-SHIV-IN−. This co-immunization elicited potent vaccine-specific CD4 and CD8 T cells both in mice and rhesus macaques. Antibody-dependent cell-mediated cytotoxicity (ADCC) antibodies were detected up to 40 weeks post-immunization in both plasma and mucosal compartments of rhesus macaques and were enhanced by the cytokines.