HIV vaccines have had limited success in human trials, and protective CD8+ T cell responses are rarely observed. In a previous vaccine trial for simian immunodeficiency virus (SIV), SIV protein-expressing rhesus cytomegalovirus strain 68-1 vectors proved successful for the generation and maintenance of broad CD8+ T cell responses. A new study now reveals that these vectors elicit SIV-specific CD8+ T cells that recognize highly diverse and promiscuous SIV epitopes, as opposed to the small range of epitopes that are targeted during natural SIV infection and elicit a narrow CD8+ T cell response which cannot fully control viral replication. The atypical vaccine response occurs because the vectors carry the gene Rh189, which suppresses the targeting of natural epitopes, and also lack Rh157.4, Rh157.5 and Rh157.6, which allows priming of CD8+ T cells by both major histocompatibility complex class I and class II molecules to induce a broad response. Corresponding genes exist in human cytomegalovirus, raising the possibility of an analogous HIV vaccine.