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Objective: We previously demonstrated that a strategy of co-immunizing cynomologous macaques with a simian/human immunodeficiency virus DNA-based vaccine and a plasmid encoding macaque interleukin (IL)-15 induces a strong CD8 + and CD4 + effector T-cell response that, upon subsequent challenge with SHIV89.6P, controls viral replication and protects immunized animals against ongoing infection. In this follow-up study, we measured viral replication 2 years after vaccination challenge and determined the mechanism by which antigen-specific CD8 + T cells suppress viral replication. Method: From the original group of 18, we assessed the immune response in the 13 surviving animals. In addition, using cM-T807, we depleted CD8 lymphocytes to assess the role CD8 cells play in suppression of viral replication. Result: We found that peripheral blood mononuclear cells from vaccinated animals had a robust simian immunodeficiency virus Gag-specific IFN-γ response. In addition, in the DNA and IL-15 group, we observed higher levels of simian immunodeficiency virus Gag-specific, proliferating CD8 + T cells. The profile of these cells revealed more central memory than effector cells. When we transiently depleted animals of CD8 + T cells, plasma viral load increased, and peak viral load was lower in the DNA and IL-15 group compared with the DNA alone and control groups. As CD8 + T cells recovered, viral replication was controlled and we observed an increase in the number of antigen-specific effector CD8 + T cells. Conclusion: We conclude that co-immunization with a simian/human immunodeficiency virus DNA-based vaccine and IL-15 achieves sustained viral suppression and that vaccine-induced CD8 + memory T cells, which differentiate into effector cells, are central to that suppression.