ABSTRACT Certain major histocompatibility complex class I (MHC-I) alleles (e.g., HLA-B*27 ) are enriched among human immunodeficiency virus type 1 (HIV-1)-infected individuals who suppress viremia without treatment (termed “elite controllers” [ECs]). Likewise, Mamu-B*08 expression also predisposes rhesus macaques to control simian immunodeficiency virus (SIV) replication. Given the similarities between Mamu-B*08 and HLA-B*27, SIV-infected Mamu-B*08 ⁺ animals provide a model to investigate HLA-B*27-mediated elite control. We have recently shown that vaccination with three immunodominant Mamu-B*08-restricted epitopes (Vif RL8, Vif RL9, and Nef RL10) increased the incidence of elite control in Mamu-B*08 ⁺ macaques after challenge with the pathogenic SIVmac239 clone. Furthermore, a correlate analysis revealed that CD8 ⁺ T cells targeting Nef RL10 was correlated with improved outcome. Interestingly, this epitope is conserved between SIV and HIV-1 and exhibits a delayed and atypical escape pattern. These features led us to postulate that a monotypic vaccine-induced Nef RL10-specific CD8 ⁺ T-cell response would facilitate the development of elite control in Mamu-B*08 ⁺ animals following repeated intrarectal challenges with SIVmac239. To test this, we vaccinated Mamu-B*08 ⁺ animals with nef inserts in which Nef RL10 was either left intact (group 1) or disrupted by mutations (group 2). Although monkeys in both groups mounted Nef-specific cellular responses, only those in group 1 developed Nef RL10-specific CD8 ⁺ T cells. These vaccine-induced effector memory CD8 ⁺ T cells did not prevent infection. Escape variants emerged rapidly in the group 1 vaccinees, and ultimately, the numbers of ECs were similar in groups 1 and 2. High-frequency vaccine-induced CD8 ⁺ T cells focused on a single conserved epitope and therefore did not prevent infection or increase the incidence of elite control in Mamu-B*08 ⁺ macaques. IMPORTANCE Since elite control of chronic-phase viremia is a classic example of an effective immune response against HIV/SIV, elucidating the basis of this phenomenon may provide useful insights into how to elicit such responses by vaccination. We have previously established that vaccine-induced CD8 ⁺ T-cell responses against three immunodominant epitopes can increase the incidence of elite control in SIV-infected Mamu-B*08 ⁺ rhesus macaques—a model of HLA-B*27-mediated elite control. Here, we investigated whether a monotypic vaccine-induced CD8 ⁺ T-cell response targeting the conserved “late-escaping” Nef RL10 epitope can increase the incidence of elite control in Mamu-B*08 ⁺ monkeys. Surprisingly, vaccine-induced Nef RL10-specific CD8 ⁺ T cells selected for variants within days after infection and, ultimately, did not facilitate the development of elite control. Elite control is, therefore, likely to involve CD8 ⁺ T-cell responses against more than one epitope. Together, these results underscore the complexity and multidimensional nature of virologic control of lentivirus infection.