Inhibitory natural killer cell receptor KIR3DL1 with its ligand Bw4 constraints HIV-1 disease among South Indians

OBJECTIVE: To investigate the role of genotypic and phenotypic characteristics of killer cell immunoglobulin-like receptors (KIRs) and their human leukocyte antigen (HLA) class-1 ligands in HIV-1 disease progression. STUDY DESIGN AND METHODS: This is a nested case-control study including 347 HIV seropositive (HIV-1+) individuals from South India constituting 45 long-term nonprogressors (LTNPs) and 302 disease progressors. KIR genotyping was performed by multiplex sequence-specific primer-directed PCR (SSP-PCR). Phenotypic expressions of KIR3DL1/S1 was studied using multiparametric flow cytometry assay. HLA-Bw4 and Bw6 epitopes were determined by ARMS-PCR. HLA-Bw4I80, HLA-Bw4T80, HLA-C1, HLA-C2, and HLA-Aw4 were genotyped using SSP-PCR. Serum levels of IFN-γ was quantified using ELISA method. RESULTS: Overall, 37 different KIR genotypes were observed and the distribution of genotypes with AB-AB (OR = 2.2, P = 0.033) constellations showed significant increase among LTNPs. The frequencies of 3DL1-2DL3-2DL5 (OR = 2.2, Pc = 0.031), 3DL1-Bw4/Aw4 (OR = 2.49, Pc = 0.019), homozygous Bw4 (OR = 2.422, Pc = 0.011) were observed higher in LTNPs and 2DS1-2DS2-2DS3 (OR = 0.475, Pc = 0.03), homozygous Bw6 (OR = 0.413, Pc = 0.011) were higher in the disease progressors. Flow cytometry assay showed the increased expression and maintenance of 3DL1/S1+NK cells in LTNPs (P = 0.0001). Further the expansion of 3DS1+NK cells was higher than 3DL1+NK cells in the heterozygous 3DL1/S1 LTNPs (P = 0.001). CONCLUSION: The inhibitory receptor 3DL1 with Bw4 and its A-haplotype defining KIR genes (2DL3/L5) confers protection against HIV-1 disease progression. An increased expression and maintenance of 3DL1/S1+ natural killer cells may contribute to the efficient activation of the natural killer cells and subsequent long-term nonprogression (LTNPn) to the disease.