Evaluation of: Böckl K, Wild J, Bredl S et al. Altering an artificial Gagpolnef polyprotein and mode of Env co-administration affects the immunogenicity of a clade C HIV-1 DNA vaccine. PLoS ONE 7(4), e34723 (2012). SIV vaccination studies in monkeys have revealed that Env-directed antibodies are critical for protection against virus acquisition, whereas CD8(+) T-cell responses against the Gag and Pol proteins contribute to control of viremia postinfection. However, designing a vaccine that strongly activates both arms of the immune system, is challenging for a variety of reasons, one being interference of Gag and Env responses. Böckl et al. have studied how to optimize CD8 T-cell responses against Gag, Pol and Nef in the presence of Env co-vaccination. Although Env coadministration suppressed anti-Gag CD8(+) responses, this effect could be counteracted by adjusting the molar ratio of the vaccines and by spatial or temporal separation of the Gag and Env antigens. These results demonstrate that optimal induction of antiviral CD8(+) responses requires careful optimization of vaccine design, composition and administration.