This study investigates the epistatic interaction between the KIR3DS1 allele and HLA-B alleles that encode molecules with isoleucine at position 80 (HLA-B Bw4-80IIe) in delaying the progression to AIDS in individuals infected with HIV-1. The research reveals that the combination of KIR3DS1 and HLA-B Bw4-80IIe alleles is strongly associated with delayed progression to AIDS. In the absence of KIR3DS1, the HLA-B Bw4-80IIe allele does not influence AIDS outcomes, while in the absence of HLA-B Bw4-80IIe, KIR3DS1 is associated with faster progression. These findings suggest an epistatic interaction between the two loci, with the strongest synergistic effect on the progression to CD4+ T-cell depletion, indicating a protective NK cell response involving KIR3DS1 and its HLA class I ligands. The KIR3DS1 gene encodes molecules with short cytoplasmic tails and a charged lysine residue in the transmembrane region, characteristic of an activating KIR. KIR3DL1, on the other hand, encodes molecules with long cytoplasmic tails that inhibit NK-cell activity upon ligand binding. The KIR3DS1 and KIR3DL1 genes are located in a genomic region that has undergone expansion and contraction over time. The study also shows that HLA-B molecules with the Bw4-80Ile genotype are more effective ligands for KIR3DL1 than those with Bw4-80Thr. The protective effect of HLA-B Bw4-80Ile is eliminated when the influence of the combined KIR3DS1 + HLA-B Bw4-80Ile genotype is considered as a covariate, indicating that the Bw4-80Ile protection is derived completely from this epistatic interaction. The study also highlights the importance of the HLA-B locus in regulating AIDS progression and the receptor-ligand relationship of HLA-B molecules with KIR3DL1. The synergistic effect of KIR3DS1 and HLA-B Bw4-80IIe was strongest in outcomes involving CD4+ T-cell counts below 200 per mm³. The findings suggest that the KIR3DS1 + HLA-B Bw4-80IIe genotype provides protection against rapid AIDS progression, and this protective effect is more pronounced in European Americans than in African Americans. The study also indicates that the protective effect of KIR3DS1 + HLA-B Bw4-80IIe may be due to a functional interaction on T cells, NK cells, or both. The results support the model in which KIR3DS1 binds HLA-B molecules containing BThis study investigates the epistatic interaction between the KIR3DS1 allele and HLA-B alleles that encode molecules with isoleucine at position 80 (HLA-B Bw4-80IIe) in delaying the progression to AIDS in individuals infected with HIV-1. The research reveals that the combination of KIR3DS1 and HLA-B Bw4-80IIe alleles is strongly associated with delayed progression to AIDS. In the absence of KIR3DS1, the HLA-B Bw4-80IIe allele does not influence AIDS outcomes, while in the absence of HLA-B Bw4-80IIe, KIR3DS1 is associated with faster progression. These findings suggest an epistatic interaction between the two loci, with the strongest synergistic effect on the progression to CD4+ T-cell depletion, indicating a protective NK cell response involving KIR3DS1 and its HLA class I ligands. The KIR3DS1 gene encodes molecules with short cytoplasmic tails and a charged lysine residue in the transmembrane region, characteristic of an activating KIR. KIR3DL1, on the other hand, encodes molecules with long cytoplasmic tails that inhibit NK-cell activity upon ligand binding. The KIR3DS1 and KIR3DL1 genes are located in a genomic region that has undergone expansion and contraction over time. The study also shows that HLA-B molecules with the Bw4-80Ile genotype are more effective ligands for KIR3DL1 than those with Bw4-80Thr. The protective effect of HLA-B Bw4-80Ile is eliminated when the influence of the combined KIR3DS1 + HLA-B Bw4-80Ile genotype is considered as a covariate, indicating that the Bw4-80Ile protection is derived completely from this epistatic interaction. The study also highlights the importance of the HLA-B locus in regulating AIDS progression and the receptor-ligand relationship of HLA-B molecules with KIR3DL1. The synergistic effect of KIR3DS1 and HLA-B Bw4-80IIe was strongest in outcomes involving CD4+ T-cell counts below 200 per mm³. The findings suggest that the KIR3DS1 + HLA-B Bw4-80IIe genotype provides protection against rapid AIDS progression, and this protective effect is more pronounced in European Americans than in African Americans. The study also indicates that the protective effect of KIR3DS1 + HLA-B Bw4-80IIe may be due to a functional interaction on T cells, NK cells, or both. The results support the model in which KIR3DS1 binds HLA-B molecules containing B