HLA alleles B57/58, B27, and B35 have the strongest genetic associations with HIV-1 disease progression. The mechanisms of these relationships may be host control of HIV-1 infection via CD8⁺ T-cell responses. We examined these immune responses in subjects from the Seattle Primary Infection Cohort with these alleles. CD8⁺ T-cell responses to conserved HIV epitopes within B57/58 alleles (TW10 and KF11) and B27 alleles (KK10 and FY10) delayed declines in CD4⁺ T-cell counts (4 to 8 times longer), while responses to variable epitopes presented by B35 alleles (DL9 and IL9) resulted in more rapid progression. The plasma viral load was higher in B57/58⁺ and B27⁺ subjects lacking the conserved B57/58- and B27-restricted responses. The presence of certain B57/58-, B27-, and B35-restricted HIV-specific CD8⁺ T-cell responses after primary HIV-1 infection better defined disease progression than the HLA genotype alone, suggesting that it is the HIV-specific CD8⁺ T cells and not the presence of a particular HLA allele that determine disease progression. Further, the most effective host CD8⁺ T-cell responses to HIV-1 were prevalent within an HLA allele, represented a high total allele fraction of the host CD8⁺ T-cell response, and targeted conserved regions of HIV-1. These data suggest that vaccine immunogens should contain only conserved regions of HIV-1.