Objective: To determine the associations of KIR3DL1/S1(3DL1/S1) and its epistatic interactions with human leukocyte antigen class I (HLA-I) alleles with resistance and susceptibility to HIV-1. Design: Despite repeated exposure to HIV-1, a subset of women enrolled in the Pumwani sex worker cohort remain HIV uninfected. Previous studies have shown that specific HLA class I and II alleles were associated with this natural immunity. In this study, we investigated the association of 3DL1/S1 and its epistatic interactions with HLA-I, with resistance or susceptibility to HIV-1 acquisition. Methods: We used a sequence-based typing method to genotype 3DL1/S1 of 641 women in this cohort. The association of 3DL1/S1 and its epistatic interactions with HLA-I were analyzed using SPSS statistics software. Results: 3DL1∗041 is enriched in the HIV-1-resistant women [P = 0.009, Pc = 0.0468, odds ratio (OR): 3.359, 95% confidence interval (CI): 1.39-8.32], whereas, 3DL1∗020 was associated with susceptibility to HIV-1 infection before correction for multiple comparisons (P = 0.029, Pc = 0.0858, OR: 0.316, 95%CI: 0.10-1.04). Epistatic interactions between several 3DL1 alleles and specific HLA-I alleles were observed. Among them the cocarriage of 3DL1∗041 with Bw4 (P = 1E - 05, Pc = 0.0015, OR: 13.33, 95%CI: 3.43-51.9), or Bw6 (P = 0.008, Pc = 0.272, OR: 3.92, 95%CI: 1.51-10.17), increased the odds of remaining HIV-1 uninfected. Further, 3DL1∗041+/Bw4+ women who entered the cohort HIV negative remained uninfected (P = 0.032, Pc = 0.0858). Cocarriage of 3DL1∗01501 with C∗02 : 10 (P = 2.73E - 07, Pc = 7.0954E - 06), B∗15 : 03 (P = 3.21E - 04, Pc = 0.0042), A24 supertype (P = 8.89E - 04, Pc = 0.0077), or A∗23 : 01 (P = 0.0036, Pc = 0.0236) was associated with increased susceptibility to seroconversion. Conclusion: The effects of interactions between 3DL1 and HLA-I alleles on resistance/susceptibility to HIV-1 infection suggest that innate immunity plays an important role in HIV-1 acquisition and should be studied and explored for HIV prevention.
