Influence of HLA class I haplotypes on HIV-1 seroconversion and disease progression in Pumwani sex worker cohort.

We examined the effect of HLA class I haplotypes on HIV-1 seroconversion and disease progression in the Pumwani sex worker cohort. This study included 595 HIV-1 positive patients and 176 HIV negative individuals. HLA-A, -B, and -C were typed to 4-digit resolution using sequence-based typing method. HLA class I haplotype frequencies were estimated using PyPop 32-0.6.0. The influence of haplotypes on time to seroconversion and CD4+ T cell decline to <200 cells/mm3 were analyzed by Kaplan-Meier analysis using SPSS 13.0. Before corrections for multiple comparisons, three 2-loci haplotypes were significantly associated with faster seroconversion, including A23∶01-C02∶02 (p = 0.014, log rank(LR) = 6.06, false-discovery rate (FDR) = 0.056), B42∶01-C17∶01 (p = 0.01, LR = 6.60, FDR = 0.08) and B07∶02-C07∶02 (p = 0.013, LR = 6.14, FDR = 0.069). Two A74∶01 containing haplotypes, A74∶01-B15∶03 (p = 0.047, LR = 3.942, FDR = 0.068) and A74∶01-B15∶03-C02∶02 (p = 0.045, LR = 4.01, FDR = 0.072) and B14∶02-C08∶02 (p = 0.021, LR = 5.36, FDR = 0.056) were associated with slower disease progression. Five haplotypes, including A30∶02-B45∶01 (p = 0.0008, LR = 11.183, FDR = 0.013), A30∶02-C16∶01 (p = 0.015, LR = 5.97, FDR = 0.048), B53∶01-C04∶01 (p = 0.010, LR = 6.61, FDR = 0.08), B15∶10-C03∶04 (p = 0.031, LR = 4.65, FDR = 0.062), and B58∶01-C03∶02 (p = 0.037, LR = 4.35, FDR = 0.066) were associated with faster progression to AIDS. After FDR corrections, only the associations of A30∶02-B45∶01 and A30∶02-C16∶01 with faster disease progression remained significant. Cox regression and deconstructed Kaplan-Meier survival analysis showed that the associations of haplotypes of A23∶01-C02∶02, B07∶02-C07∶02, A74∶01-B15∶03, A74∶01-B15∶03-C02∶02, B14∶02-C08∶02 and B58∶01-C03∶02 with differential seroconversion or disease progression are due to the dominant effect of a single allele within the haplotypes. The true haplotype effect was observed with A30∶02-B45∶01, A30∶02-C16∶02, B53∶01-C04∶01 B15∶10-C03∶04, and B42∶01-C*17∶01. In these cases, the presence of both alleles accelerated the disease progression or seroconversion than any of the single allele within the haplotypes. Our study showed that the true effects of HLA class I haplotypes on HIV seroconversion and disease progression exist and the associations of HLA class I haplotype can also be due to the dominant effect of a single allele within the haplotype.