Collectively, these data demonstrated that DM-UFO vaccination significantly delayed acquisition of SHIV1157ipd3N4 infection relative to unvaccinated Mamu-A*01- RMs, and suggested that the vaccine-induced Env-specific CD8 T cells contributed to enhanced protection while vaccine-induced Gag and Env-specific CD4 T cell responses contributed to diminished protection. Here, CD4 is linked to infection.