The human leukocyte antigen (HLA) B57 allele and the closely related HLA-B5801 allele are overrepresented among human immunodeficiency virus type 1 (HIV-1)-infected individuals with a long-term nonprogressive clinical course of disease (known as "long-term nonprogressors" [LTNPs]). These alleles are, however, also present among individuals with normal disease progression (known as "progressors"). In a comparison of HLA-B57/5801-expressing progressors and LTNPs, we observed a similar prevalence of escape mutations in 4 Nef epitopes and a similar reactivity of CD8+ T cells against 3 of 4 of these epitopes and their autologous escape variants. However, LTNPs tended to have frequent and preserved CD8+ T cell interferon-gamma responses against the wild-type HW9 Nef epitope, whereas progressors did not maintain a specific CD8+ T cell response. This finding is in line with the findings of a more exhausted phenotype of CD8+ T cells in progressors, as is demonstrated by their enhanced level of expression of inhibitory receptor "programmed death 1" (PD-1). The results of the present study suggest that preservation of HW9-specific T cell responses is associated with a more benign clinical course of infection.