The authors have declared that no competing interests exist.
Conceived and designed the experiments: ML. Performed the experiments: HOP LM TB. Analyzed the data: RS HOP ML. Contributed reagents/materials/analysis tools: JK CW EN FAP ML. Wrote the paper: RS HOP ML.
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 A*23∶01-C*02∶02 (p = 0.014, log rank(LR) = 6.06, false-discovery rate (FDR) = 0.056), B*42∶01-C*17∶01 (p = 0.01, LR = 6.60, FDR = 0.08) and B*07∶02-C*07∶02 (p = 0.013, LR = 6.14, FDR = 0.069). Two A*74∶01 containing haplotypes, A*74∶01-B*15∶03 (p = 0.047, LR = 3.942, FDR = 0.068) and A*74∶01-B*15∶03-C*02∶02 (p = 0.045, LR = 4.01, FDR = 0.072) and B*14∶02-C*08∶02 (p = 0.021, LR = 5.36, FDR = 0.056) were associated with slower disease progression. Five haplotypes, including A*30∶02-B*45∶01 (p = 0.0008, LR = 11.183, FDR = 0.013), A*30∶02-C*16∶01 (p = 0.015, LR = 5.97, FDR = 0.048), B*53∶01-C*04∶01 (p = 0.010, LR = 6.61, FDR = 0.08), B*15∶10-C*03∶04 (p = 0.031, LR = 4.65, FDR = 0.062), and B*58∶01-C*03∶02 (p = 0.037, LR = 4.35, FDR = 0.066) were associated with faster progression to AIDS. After FDR corrections, only the associations of A*30∶02-B*45∶01 and A*30∶02-C*16∶01 with faster disease progression remained significant. Cox regression and deconstructed Kaplan-Meier survival analysis showed that the associations of haplotypes of A*23∶01-C*02∶02, B*07∶02-C*07∶02, A*74∶01-B*15∶03, A*74∶01-B*15∶03-C*02∶02, B*14∶02-C*08∶02 and B*58∶01-C*03∶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 A*30∶02-B*45∶01, A*30∶02-C*16∶02, B*53∶01-C*04∶01 B*15∶10-C*03∶04, and B*42∶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.
HIV/AIDS continues to be a major public health concern, though decline in HIV prevalence has been reported for certain regions
Human leukocyte antigen (HLA) class I and II molecules present peptides to CD8+ and CD4+ T cells respectively
Informed written consent was obtained from all study subjects and the Ethics Committee of the University of Manitoba as well as Ethics and Research Committee of Kenyatta National Hospital have approved this study.
The subjects involved in this study are enrollees of Pumwani sex worker Cohort, an open cohort with biannual follow-ups, established in 1985 in Nairobi, Kenya
Human leukocyte antigen class I typing was performed as described earlier
HLA class I haplotype frequencies were estimated using PyPop version 32-0.6.0
To examine whether the significant association of haplotypes with seroconversion or disease progression is due to individual allele or haplotype effect, we conducted
Two and three loci haplotypes of the 3 classical HLA class I genes were identified using 771 women enrolled in Pumwani sex worker cohort. Haplotypes occurred at frequencies above 1% is provided in
HLA-A-B Haplotype | Frequency (%)(2n = 1458) | Phenotype Frequency (%)(n = 736) |
A*30∶01-B*42∶01 | 53 (3.6) | 54 (7.3) |
A*66∶01-B*58∶02 | 37 (2.5) | 39 (5.3) |
A*02∶02-B*58∶02 | 34 (2.3) | 35 (4.8) |
A*36∶01-B*53∶01 | 28 (1.9) | 27 (3.7) |
A*01∶01-B*81∶01 | 26 (1.8) | 30 (4.1) |
A*02∶01-B*15∶03 | 25 (1.7) | 30 (4.1) |
A*74∶01-B*58∶02 | 23 (1.6) | 33 (4.5) |
A*74∶01-B*15∶03 | 22 (1.5) | 21 (2.9) |
A*68∶02-B*15∶10 | 21 (1.4) | 25 (3.4) |
A*30∶02-B*57∶03 | 17 (1.2) | 30 (4.1) |
A*03∶01-B*49∶01 | 15 (1.0) | 17 (2.3) |
A*68∶02-B*42∶01 | 15 (1.0) | 20 (2.7) |
A*30∶02-B*45∶01 | 15 (1.0) | 19 (2.6) |
Note: The ‘n’ represents the number of subjects studied; ‘2n’ indicates number of chromosomes; Numbers in parentheses represent percent frequency.
HLA-B-HLA-C Haplotype | Frequency (%)(2n = 1398) | Phenotype Frequency(%)(n = 724) |
B*58∶02-C*06∶02 | 121 (8.7) | 120 (16.6) |
B*42∶01-C*17∶01 | 99 (7.1) | 98 (13.5) |
B*15∶03-C*02∶02 | 90 (6.4) | 87 (12.0) |
B*53∶01-C*04∶01 | 80 (5.7) | 78 (10.8) |
B*49∶01-C*07∶01 | 63 (4.5) | 61 (8.4) |
B*15∶10-C*03∶04 | 57 (4.1) | 58 (8.0) |
B*81∶01-C*18∶01 | 39 (2.8) | 39 (5.4) |
B*45∶01-C*16∶01 | 37 (2.6) | 35 (4.8) |
B*07∶02-C*07∶02 | 28 (2.0) | 29 (4.0) |
B*57∶02-C*18∶01 | 26 (1.9) | 26 (3.6) |
B*57∶03-C*07∶01 | 25 (1.8) | 27 (3.7) |
B*35∶01-C*04∶01 | 21 (1.5) | 20 (2.8) |
B*13∶02-C*06∶02 | 21 (1.5) | 21 (2.9) |
B*18∶01-C*07∶04 | 21 (1.5) | 21 (2.9) |
B*58∶01-C*07∶01 | 19 (1.4) | 25 (3.5) |
B*57∶03-C*18∶01 | 19 (1.4) | 21 (2.9) |
B*14∶06-C*08∶02 | 19 (1.4) | 19 (2.6) |
B*44∶03-C*04∶01 | 19 (1.4) | 21 (2.9) |
B*58∶01-C*06∶02 | 19 (1.4) | 18 (2.5) |
B*14∶02-C*08∶02 | 18 (1.3) | 18 (2.5) |
B*44∶15-C*04∶07 | 18 (1.3) | 18 (2.5) |
B*51∶01-C*16∶01 | 18 (1.3) | 18 (2.5) |
B*45∶01-C*06∶02 | 18 (1.3) | 18 (2.5) |
B*15∶03-C*04∶01 | 17 (1.2) | 20 (2.8) |
B*58∶01-C*03∶02 | 16 (1.1) | 16 (2.2) |
Note: The ‘n’ represents the number of subjects studied; ‘2n’ indicates number of chromosomes; Numbers in parentheses represent percent frequency.
HLA-A-HLA-C haplotype | Frequency (%) (2n = 1402) | Phenotype Frequency (%) (n = 726) |
A*30∶01-C*17∶01 | 63 (4.5) | 64 (8.8) |
A*66∶01-C*06∶02 | 42 (3.0) | 45 (6.2) |
A*02∶02-C*06∶02 | 38 (2.7) | 42 (5.8) |
A*01∶01-C*18∶01 | 34 (2.4) | 39 (5.4) |
A*36∶01-C*04∶01 | 29 (2.1) | 28 (3.9) |
A*02∶01-C*16∶01 | 27 (1.9) | 28 (3.9) |
A*74∶01-C*06∶02 | 25 (1.8) | 40 (5.5) |
A*68∶02-C*03∶04 | 24 (1.7) | 27 (3.7) |
A*74∶01-C*02∶02 | 23 (1.6) | 21 (2.9) |
A*74∶01-C*07∶01 | 22 (1.6) | 30 (4.1) |
A*02∶01-C*04∶01 | 22 (1.6) | 32 (4.4) |
A*30∶02-C*18∶01 | 22 (1.6) | 26 (3.6) |
A*03∶01-C*07∶01 | 21 (1.5) | 26 (3.6) |
A*02∶01-C*02∶02 | 20 (1.4) | 26 (3.6) |
A*23∶01-C*02∶02 | 19 (1.4) | 21 (2.9) |
A*01∶01-C*07∶01 | 19 (1.4) | 19 (2.6) |
A*68∶02-C*07∶01 | 19 (1.4) | 23 (3.2) |
A*74∶01-C*04∶01 | 18 (1.3) | 21 (2.9) |
A*30∶02-C*04∶01 | 16 (1.1) | 25 (3.4) |
A*30∶02-C*16∶01 | 16 (1.1) | 15 (2.1) |
A*30∶02-C*07∶04 | 15 (1.1) | 14 (1.9) |
A*68∶02-C*07∶02 | 15 (1.1) | 17 (2.3) |
A*02∶01-C*07∶01 | 15 (1.1) | 20 (2.8) |
Note: The ‘n’ represents the number of subjects studied; ‘2n’ indicates number of chromosomes; Numbers in parentheses represent percent frequency.
HLA-A-B-C haplotype | Frequency(%) | PhenotypeFrequency |
(2n = 1388) | (n = 721) | |
A*30∶01-B*42∶01-C*17∶01 | 53 (3.8) | 53 (7.4) |
A*66∶01-B*58∶02-C*06∶02 | 36 (2.6) | 36 (5.0) |
A*02∶02-B*58∶02-C*06∶02 | 31 (2.2) | 31 (4.3) |
A*36∶01-B*53∶01-C*04∶01 | 27 (1.9) | 26 (3.6) |
A*74∶01-B*58∶02-C*06∶02 | 23 (1.7) | 28 (3.9) |
A*01∶01-B*81∶01-C*18∶01 | 22 (1.6) | 23 (3.2) |
A*74∶01-B*15∶03-C*02∶02 | 20 (1.4) | 17 (2.4) |
A*02∶01-B*15∶03-C*02∶02 | 20 (1.4) | 22 (3.1) |
A*68∶02-B*15∶10-C*03∶04 | 19 (1.4) | 21 (2.9) |
A*03∶01-B*49∶01-C*07∶01 | 15 (1.1) | 16 (2.2) |
A*74∶01-B*49∶01-C*07∶01 | 15 (1.1) | 14 (1.9) |
Note: The ‘n’ represents the number of subjects studied; ‘2n’ indicates number of chromosomes; Numbers in parentheses represent percent frequency.
Survival analyses with 331 HIV negative and seroconverters identified the association of three 2 loci haplotypes, A*23∶01-C*02∶02 (p = 0.014, log rank (LR) = 6.06), B*42∶01-C*17∶01 (p = 0.01, LR = 6.60) and B*07∶02-C*07∶02 (p = 0.013, LR = 6.14) with faster seroconversion (
(A) A*23∶01-C*02∶02; (B) A*23∶01; (C) C*02∶02; (D) B*42∶01-C*17∶01; (E) B*42∶01; (F) C*17∶01; (G) B*07∶02-C*07∶02; (H) B*07∶02; (I) C*07∶02. Solid line represents women with the specific haplotype or allele. Dashed line represents women without the specific haplotype or allele.
Haplotype | Phenotype | Log Rank | P value | FDR | association |
Frequency (%) | |||||
A*23∶01-C*02∶02 | 2.9 | 6.06 | 0.014 | 0.056 | faster seroconversion |
B*07∶02-C*07∶02 | 4 | 6.14 | 0.013 | 0.069 | faster seroconversion |
B*42∶01-C*17∶01 | 13.5 | 6.6 | 0.01 | 0.080 | faster seroconversion |
A*74∶01-B*15∶03 | 2.9 | 3.942 | 0.047 | 0.068 | slower disease progression |
A*74∶01-B*15∶03-C*02∶02 | 2.4 | 4.007 | 0.045 | 0.072 | slower disease progression |
B*14∶02-C*08∶02 | 2.5 | 5.364 | 0.021 | 0.056 | slower disease progression |
A*30∶02-B*45∶01 | 2.6 | 11.183 | 0.0008 | faster disease progression | |
B*53∶01-C*04∶01 | 10.8 | 6.612 | 0.01 | 0.080 | faster disease progression |
B*15∶10-C*03∶04 | 8 | 4.648 | 0.031 | 0.062 | faster disease progression |
B*58∶01-C*03∶02 | 2.2 | 4.349 | 0.037 | 0.066 | faster disease progression |
A*30∶02-C*16∶01 | 2.1 | 5.966 | 0.015 | faster disease progression |
Three A-B, B-C, or A-B-C haplotypes were associated with slower disease progression to CD4<200 cells/mm3 (
(A) A*74∶01-B*15∶03; (B) A*74∶01; (C) B*15∶03; (D) A*74∶01-B*15∶03-C*02∶02; (E) A*74∶01; (F) C*02∶02; (G) B*14∶02-C*08∶02; (H) B*14∶02; (I) C*08∶02. Solid line represents women with the specific haplotype or allele. Dashed line represents women without the specific haplotype or allele.
(A) A*30∶02-B*45∶01; (B) A*30∶02; (C) B*45∶01; (D) A*30∶02-C*16∶01; (E) A*30∶02; (F) C*16∶01; (G) B*53∶01-C*04∶01; (H) B*53∶01; (I) C*04∶01; (J) B*15∶10-C*03∶04; (K) B*15∶10; (L) C*03∶04; (M) B*58∶01-C*03∶02; (N) B*58∶01; (O) C*03∶02. Solid line represents women with the specific haplotype or allele. Dashed line represents women without the specific haplotype or allele.
Subsequent to the identification of haplotypes associated with either HIV-1 seroconversion or disease progression, we attempted to dissect whether the observed association is due to haplotype effect or the predominant effect by any of the constituent alleles using deconstructed Kaplan-Meier analysis and backward conditional Cox regression analysis. The analysis showed that the association of A*23∶01-C*02∶02 (p = 0.014, LR = 6.06) with rapid seroconversion could be attributed to A*23∶01 (p = 0.005, LR = 7.92) and not C*02∶02 (p = 0.108, LR = 2.58) (
Variables in the Equation | |||||||||
A*23∶01-C*02∶02 | −0.2310 | 0.5142 | 0.2018 | 1 | 0.6533 | 0.7937 | 0.2897 | 2.1745 | |
A*23∶01 | −0.5061 | 0.2767 | 3.3460 | 1 | 0.0674 | 0.6028 | 0.3505 | 1.0368 | |
C*02∶02 | −0.1872 | 0.2690 | 0.4845 | 1 | 0.4864 | 0.8292 | 0.4894 | 1.4049 | |
A*23∶01 | −0.5704 | 0.2314 | 6.0773 | 1 | 0.0137 | 0.5653 | 0.3592 | 0.8897 | |
C*02∶02 | −0.2482 | 0.2273 | 1.1930 | 1 | 0.2747 | 0.7802 | 0.4997 | 1.2180 | |
A*23∶01 | −0.6096 | 0.2282 | 7.1378 | 1 | 0.0075 | 0.5436 | 0.3476 | 0.8501 | |
B*42∶01-C*17∶01 | −8.7896 | 43.6369 | 0.0406 | 1 | 0.8404 | 0.0002 | 1.094E−41 | 2.121E+33 | |
B*42∶01 | 8.0026 | 43.6350 | 0.0336 | 1 | 0.8545 | 2988.8021 | 2.154E−34 | 4.147E+40 | |
C*17∶01 | 0.2749 | 0.3666 | 0.5626 | 1 | 0.4532 | 1.3165 | 0.6418 | 2.7004 | |
B*42∶01-C*17∶01 | −0.9041 | 0.4278 | 4.4673 | 1 | 0.0346 | 0.4049 | 0.1751 | 0.9364 | |
B*17∶01 | 0.3713 | 0.3903 | 0.9053 | 1 | 0.3414 | 1.4497 | 0.6746 | 3.1152 | |
B*42∶01-C*17∶01 | −0.5600 | 0.2210 | 6.4236 | 1 | 0.0113 | 0.5712 | 0.3704 | 0.8808 | |
B*07∶02-C*07∶02 | 0.4356 | 0.7551 | 0.3327 | 1 | 0.5641 | 1.5458 | 0.3519 | 6.7910 | |
B*07∶02 | −0.7345 | 0.4185 | 3.0801 | 1 | 0.0793 | 0.4798 | 0.2112 | 1.0896 | |
C*07∶02 | −0.6586 | 0.5103 | 1.6656 | 1 | 0.1968 | 0.5176 | 0.1904 | 1.4072 | |
B*07∶02 | −0.5992 | 0.3689 | 2.6379 | 1 | 0.1043 | 0.5493 | 0.2665 | 1.1319 | |
C*07∶02 | −0.4510 | 0.3987 | 1.2793 | 1 | 0.2580 | 0.6370 | 0.2916 | 1.3917 | |
B*07∶02 | −0.8318 | 0.2918 | 8.1247 | 1 | 0.0044 | 0.4353 | 0.2457 | 0.7712 |
Variables in the Equation | |||||||||
A*74∶01-B*15∶03 | 0.6331 | 0.6723 | 0.8870 | 1 | 0.3463 | 1.8835 | 0.5044 | 7.0340 | |
A*74∶01 | 0.4074 | 0.2734 | 2.2198 | 1 | 0.1362 | 1.5029 | 0.8794 | 2.5685 | |
B*15∶03 | 0.1235 | 0.2360 | 0.2741 | 1 | 0.6006 | 1.1315 | 0.7125 | 1.7968 | |
A*74∶01-B*15∶03 | 0.7508 | 0.6334 | 1.4050 | 1 | 0.2359 | 2.1186 | 0.6122 | 7.3313 | |
A*74∶01 | 0.3941 | 0.2724 | 2.0936 | 1 | 0.1479 | 1.4830 | 0.8696 | 2.5293 | |
A*74∶01 | 0.5650 | 0.2510 | 5.0681 | 1 | 0.0244 | 1.7594 | 1.0758 | 2.8773 | |
A*30∶02-B*45∶01 | −1.5378 | 0.5964 | 6.6496 | 1 | 0.0099 | 0.2149 | 0.0668 | 0.6914 | |
A*30∶02 | 0.1848 | 0.2422 | 0.5824 | 1 | 0.4454 | 1.2030 | 0.7484 | 1.9338 | |
B*45∶01 | −0.0410 | 0.3029 | 0.0183 | 1 | 0.8923 | 0.9598 | 0.5301 | 1.7378 | |
A*30∶02-B*45∶01 | −1.5792 | 0.5123 | 9.5031 | 1 | 0.0021 | 0.2061 | 0.0755 | 0.5626 | |
A*30∶02 | 0.1884 | 0.2406 | 0.6132 | 1 | 0.4336 | 1.2074 | 0.7534 | 1.9350 | |
A*30∶02-B*45∶01 | −1.4143 | 0.4659 | 9.2141 | 1 | 0.0024 | 0.2431 | 0.0975 | 0.6059 | |
A*30∶02-C*16∶01 | −0.9691 | 0.6057 | 2.5597 | 1 | 0.1096 | 0.3794 | 0.1158 | 1.2437 | |
A*30∶02 | 0.1022 | 0.2379 | 0.1845 | 1 | 0.6676 | 1.1076 | 0.6948 | 1.7656 | |
C*16∶01 | −0.3218 | 0.2478 | 1.6875 | 1 | 0.1939 | 0.7248 | 0.4460 | 1.1779 | |
A*30∶02-C*16∶01 | −0.8658 | 0.5560 | 2.4251 | 1 | 0.1194 | 0.4207 | 0.1415 | 1.2509 | |
C*16∶01 | −0.3379 | 0.2451 | 1.8999 | 1 | 0.1681 | 0.7133 | 0.4411 | 1.1532 | |
A*30∶02-C*16∶01 | −1.1684 | 0.5125 | 5.1967 | 1 | 0.0226 | 0.3109 | 0.1138 | 0.8489 | |
B*53∶01-C*04∶01 | −0.4123 | 0.5419 | 0.5789 | 1 | 0.4467 | 0.6621 | 0.2289 | 1.9151 | |
B*53∶01 | −0.0749 | 0.4585 | 0.0267 | 1 | 0.8702 | 0.9278 | 0.3777 | 2.2789 | |
C*04∶01 | −0.0799 | 0.2302 | 0.1203 | 1 | 0.7287 | 0.9232 | 0.5879 | 1.4498 | |
B*53∶01-C*04∶01 | −0.4872 | 0.2895 | 2.8326 | 1 | 0.0924 | 0.6144 | 0.3484 | 1.0835 | |
B*04∶01 | −0.0766 | 0.2293 | 0.1117 | 1 | 0.7382 | 0.9262 | 0.5909 | 1.4519 | |
B*53∶01-C*04∶01 | −0.5511 | 0.2183 | 6.3757 | 1 | 0.0116 | 0.5763 | 0.3757 | 0.8840 | |
B*15∶10-C*03∶04 | 2.024 | 1.022 | 3.9220 | 1 | 0.0477 | 7.571 | 1.021 | 56.142 | |
B*15∶10 | −0.635 | 0.710 | 0.798 | 1 | 0.3716 | 0.530 | 0.132 | 2.133 | |
C*03∶04 | −0.974 | 0.710 | 1.8819 | 1 | 0.1701 | 0.378 | 0.094 | 1.518 | |
B*15∶10-C*03∶04 | 1.389 | 0.735 | 3.5749 | 1 | 0.0587 | 4.012 | 0.950 | 16.936 | |
C*03∶04 | −0.958 | 0.710 | 1.8571 | 1 | 0.1730 | 0.380 | 0.095 | 1.528 | |
B*15∶10-C*03∶04 | 0.436 | 0.207 | 4.444 | 1 | 0.035 | 1.546 | 1.031 | 2.319 | |
B*14∶02-C*08∶02 | 1.0750 | 1.0959 | 0.9622 | 1 | 0.3266 | 2.9300 | 0.3420 | 25.1022 | |
B*14∶02 | . | 0a | . | ||||||
C*08∶02 | 0.9574 | 0.4548 | 4.4314 | 1 | 0.0353 | 2.6050 | 1.0682 | 6.3525 | |
C*08∶02 | 1.2357 | 0.4168 | 8.7882 | 1 | 0.0030 | 3.4408 | 1.5200 | 7.7888 | |
a. Degree of freedom reduced because of constant or linearly dependent covariates | |||||||||
B*58∶01-C*03∶02 | −0.0798 | 1.1406 | 0.0049 | 1 | 0.9442 | 0.9233 | 0.0987 | 8.6350 | |
B*58∶01 | −0.0759 | 0.3132 | 0.0588 | 1 | 0.8084 | 0.9269 | 0.5017 | 1.7123 | |
C*03∶02 | −0.7667 | 1.0055 | 0.5813 | 1 | 0.4458 | 0.4646 | 0.0647 | 3.3340 | |
B*58∶01 | −0.0821 | 0.2999 | 0.0749 | 1 | 0.7844 | 0.9212 | 0.5118 | 1.6582 | |
C*03∶02 | −0.8281 | 0.4757 | 3.0302 | 1 | 0.0817 | 0.4369 | 0.1720 | 1.1099 | |
C*03∶02 | −0.8894 | 0.4191 | 4.5037 | 1 | 0.0338 | 0.4109 | 0.1807 | 0.9343 | |
A*74∶01-B*15∶03-C*02∶02 | 0.6435 | 0.6780 | 0.9010 | 1 | 0.3425 | 1.9032 | 0.5040 | 7.1870 | |
A*74∶01 | 0.3874 | 0.2738 | 2.0022 | 1 | 0.1571 | 1.4732 | 0.8614 | 2.5195 | |
B*15∶03 | 0.0946 | 0.3054 | 0.0960 | 1 | 0.7567 | 1.0992 | 0.6042 | 2.0000 | |
C*02∶02 | 0.0480 | 0.2901 | 0.0274 | 1 | 0.8686 | 1.0492 | 0.5942 | 1.8526 | |
A*74∶01-B*15∶03-C*02∶02 | 0.6580 | 0.6721 | 0.9582 | 1 | 0.3276 | 1.9308 | 0.5172 | 7.2088 | |
A*74∶01 | 0.3849 | 0.2734 | 1.9824 | 1 | 0.1591 | 1.4695 | 0.8599 | 2.5111 | |
B*15∶03 | 0.1268 | 0.2360 | 0.2889 | 1 | 0.5909 | 1.1352 | 0.7149 | 1.8027 | |
A*74∶01-B*15∶03-C*02∶02 | 0.7785 | 0.6333 | 1.5110 | 1 | 0.2190 | 2.1783 | 0.6295 | 7.5372 | |
A*74∶01 | 0.3714 | 0.2723 | 1.8598 | 1 | 0.1726 | 1.4498 | 0.8501 | 2.4724 | |
A*74∶01 | 0.5506 | 0.2510 | 4.8138 | 1 | 0.0282 | 1.7343 | 1.0605 | 2.8362 |
Notable haplotype effect was observed while dissecting four haplotypes associated with the rapid disease progression. While A*30∶02 (p = 0.92, LR = 0.011) and B*45∶01 (p = 0.22, LR = 1.48) alone did not demonstrate any detrimental effect, study subjects with A*30∶02-B*45∶01 haplotype progressed to AIDS rapidly (p = 0.0008, LR = 11.18) (
HLA class I alleles, especially those from HLA-A, -B and -C loci, have been repeatedly shown to exert profound influence over the observed inter-individual variability in vulnerability to infection and disease progression among HIV exposed individuals
Our study has shown the significant influence of 11 2-loci and 3-loci haplotypes on HIV seroconversion and disease progression before correction for multiple comparisons. Faster HIV-1 seroconversion was observed in individuals possessing three 2-loci haplotypes, namely, A*23∶01-C*02∶02, B*42∶01-C*17∶01 and B*07∶02-C*07∶02. Three haplotypes (A*74∶01-B*15∶03, B*14∶02-C*08∶02, and A*74∶01-B*15∶03-C*02∶02) were associated with slower disease progression and 5 haplotypes (A*30∶02-B*45∶01, A*30∶02-C*16∶01, B*53∶01-C*04∶01, B*15∶10-C*03∶04, and B*58∶01-C*03∶02) were associated with rapid disease progression. Most of these haplotypes contained alleles previously identified to be associated with differential susceptibility to seroconversion or disease progression, such as A*23∶01, B*42∶01, B*07∶02, A*74∶01, B*14, B*15∶10, B*53∶01, and C*08∶02
We have not observed haplotype effect on slower seroconversion although several HLA class I alleles have been identified to be associated with slower seroconversion, such as A*01, C*06∶02 and C*07∶01
We used a deconstructed Kaplan-Meier analysis and Cox regression analysis to find out whether the associations of HLA class I haplotypes with differential susceptibility to HIV-1 infection and disease progression are the effect of haplotype or the constituent alleles. The analysis showed that the observed associations of these haplotypes with HIV seroconversion or disease progression can be attributed to either true haplotype effect or the dominant effect of a single allele within the haplotype. Haplotype effect has been observed in A*30∶02-B*45∶01, A*30∶02-C*16∶01, B*53∶01-C*04∶01 and B*15∶10-C*03∶04 for rapid disease progression, and B*42∶01-C*17∶01 for faster seroconversion. Although the associations of B*53∶01, B*15∶10 and B*42∶01 at the alleles level have been observed in our previous study
We have shown the correlative relationships of HLA class I haplotypes to both HIV-1 seroconversion and disease progression in Pumwani sex worker cohort. Haplotype analyses, including assessment of their constituent alleles, with two different survival end-points, time to seroconversion (in a subset of HIV negative and seroconverters) and CD4 decline (CD4<200 cells/mm3; in a subset of HIV positive and seroconverters) showed that haplotypes influencing seroconversion were not the ones impacting disease progression, reaffirming our observation in the allele level association study
The 6 alleles of three classical HLA class I genes restrict each individual’s CD8+ T cell responses to HIV-1 infection and disease progression. It is reasonable to assume that the outcome of HIV-1 infection and disease progression is influenced by CD8+ T cell responses restricted by all 6 class I alleles, each with varying effect. The alleles with dominant effect are most likely to be identified in association studies with phenotypically well-defined patient populations. Studying the effect of combinations of alleles or haplotypes on differential susceptibility to HIV-1 infection and disease progression is one step forward towards the understanding of the interactive effect of CD8+ T cell responses restricted by different HLA class I alleles. Although we cannot exclude the effect of non-HLA genes within the haplotypes, it appears that the associations of haplotypes with HIV-1 infection or disease progression in our study are either due to the dominant effect of a single allele or synergy of different alleles.
The sample size of phenotypically well-defined population is the major limiting factor in studying the effect of HLA class I haplotypes on HIV-1 infection and disease progression, given the extremely polymorphic nature of HLA class I genes. It is likely that some haplotype effects have been missed because of the sample size limitation of the study population. Despite this, our study has identified associations of HLA haplotypes with HIV seroconversion and disease progression, as well as validated some of previous findings in different populations. We hope that some of the results of our study can be confirmed by future studies of different patient populations.
Dr Nico J. D. Nagelkerke (Department of Community Medicine, UAE University, P. O. Box 17666, Al Ain, United Arab Emirates) was consulted for statistical analysis. John Rutherford and Leslie Slaney provided technical support. We thank the nurses and staff members working in the Pumwani sex worker cohort (Jane Njoki, Jane Kamene, Elizabeth Bwibo and Edith Amatiwa), for their dedication towards this research. The women enrolled in the Pumwani sex worker cohort have made vital contributions to this research.